Tetrasubstituted benzenes

ABSTRACT

Tetrasubstituted benzenes that act as modulators of gamma secretase and their use in the treatment of one or more symptoms of treating neurodegenerative disorders, e.g., Alzheimer&#39;s disease, are described.

RELATED APPLICATION INFORMATION

This application claims priority to U.S. provisional application Ser. No. 61/015,605, filed Dec. 20, 2007, and to U.S. provisional application Ser. No. 61/109,665, filed Oct. 30, 2008, both of which are herein incorporated by reference.

BACKGROUND

Alzheimer's disease (AD) is the most prevalent form of dementia. It is a neurodegenerative disorder that is associated (though not exclusively) with aging. The disorder is clinically characterized by a progressive loss of memory, cognition, reasoning and judgment that leads to an extreme mental deterioration and ultimately death. The disorder is pathologically characterized by the deposition of extracellular plaques and the presence of neurofibrillary tangles. These plaques are considered to play an important role in the pathogenesis of the disease.

These plaques mainly comprise of fibrillar aggregates of β-amyloid peptide (Aβ), which are products of the amyloid precursor protein (APP), a 695 amino-acid protein. APP is initially processed by β-secretase forming a secreted peptide and a membrane bound C99 fragment. The C99 fragment is subsequently processed by the proteolytic activity of γ-secretase. Multiple sites of proteolysis on the C99 fragment lead to the production of a range of smaller peptides (Aβ 37-42 amino acids). N-terminal truncations can also be found e.g. Aβ(4-42, 11-42) for convenience Aβ40 and Aβ42 as used herein incorporates these N-terminal truncated peptides. Upon secretion, the Aβ peptides initially form soluble aggregates which ultimately lead to the formation of insoluble deposits and plaques. Aβ42 is believed to be the most neurotoxic, the shorter peptides have less propensity to aggregate and form plaques. The Aβ plaques in the brain are also associated with cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, multi infarct dementia, dementia pugilistisca, inclusion body myositis and Down's Syndrome.

γ-secretase is an association of four proteins: Aph1, Nicastrin, Presenillin and Pen-2 (review De Strooper 2003, Neuron 38, 9). Aβ42 is selectively increased in patients carrying particular mutations in one of these components, presenilin. These mutations are correlated with early onset a familial AD. Inhibition of γ-secretase resulting in the lowering of Aβ42 is a desirable activity for the pharmaceutical community and numerous inhibitors have been found, e.g., Thompson et at (Bio. Org. and Med. Chem. Letters 2006, 16, 2357-63), Shaw et al (Bio. Org. and Med. Chem. Letters 2006, 17, 511-16) and Asberom et at (Bio. Org. and Med. Chem. Letters 2007, 15, 2219-2223). Inhibition of γ-secretase though is not without side-effects, some of which are due to the γ-secretase complex processing substrates other than C99, for e.g. Notch. A more desirable approach is to modulate the proteolytic activity of the γ-secretase complex in a manner that lowers Aβ42 in favor of shorter peptides without significantly affecting the activity of γ-secretase on substrates such as Notch.

Compounds that have shown modulation of γ-secretase include certain non-steroidal, anti-inflammatory drugs (NSAIDs), for example Flurbiprofen, (Stock et at Bio. Org. and Med. Chem. Letters 2006, 16, 2219-2223). Other publications that disclose agents said to reduce Aβ42 through the modulation of γ-secretase include: WO 04/074232, WO 05/054193, Perreto et at Journal of Medicinal Chemistry 2005, 48 5705-20, WO05/108362, WO 06/008558, WO 06/021441, WO 06/041874, WO 06/045554, WO04110350, WO 06/043964, WO 05/115990, EP1847524, WO 07/116,228, WO 07/110,667, WO 07/124,394, EP184752, EP 01849762, WO 07/125,364.

SUMMARY

Described herein are tetrasubstituted benzene compounds of formulas (I) and (II) and pharmaceutically acceptable salts thereof

Wherein:

A is CO₂H or tetrazole; R₁ and R₂ are independently selected from: (a) H, (b) F, (c) OH, (d) OR₆, (e) SR₆, (f) NHR₇, (g) N(R₇)₂ (h) NHC(O)R₆, (i) NHCO₂R₆, (j) (C₂-C₆)alkyl, (k) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, (l) C₁-C₆ alkyl that is independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)₂— groups, (m) (C₃-C₇)cycloalkyl, (n) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, (o) heterocycloalkylalky and (p) (CH₂)_(n)Q wherein n=0-2 and wherein Q is a mono- or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, and wherein Q is optionally independently substituted with up to 3 groups selected from alkyl, halogen, CF₃, OH, OCF₃, alkoxy, OCH₂CH₂OCH₃, NH₂, alkylamino, dialkylamino, morpholino, CN, NO₂, alkylthio and alkylsulfonyl,

and wherein each alkyl or cycloalkyl of R₁ and R₂ is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl,

provided that both R₁ and R₂ are not H,

or R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl or R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl ring substituted with R₂₀ and R₂₁ where R₂₀ and R₂₁ are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl R₆ is selected from:

(a) C₁-C₆ alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O), or —S(O)₂— groups,

(b) (C₃-C₇)cycloalkyl,

(c) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, (d) heterocycloalkylalky and

(e) (CH₂)_(n)Q wherein n=0-2 and wherein Q is a mono- or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, and wherein Q is optionally independently substituted with up to 3 groups selected from alkyl, halogen, CF₃, OH, OCF₃, alkoxy, OCH₂CH₂OCH₃, NH₂, alkylamino, dialkylamino, morpholino, CN, NO₂, alkylthio and alkylsulfonyl;

R₇ is independently chosen from alkyl, alkoxyethyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl or (CH₂)_(n)Q, wherein n=0-2 and wherein Q is a mono or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C and wherein Q is optionally substituted with up to 3 groups independently selected from alkyl, halogen, CF₃, OH, OCF₃, alkoxy, OCH₂CH₂OCH₃, NH₂, alkylamino, dialkylamino, morpholino, CN, NO₂, alkylthio, alkylsulfonyl; or in the case when two R₇ are attached to the same N and are both alkyl, they can be taken together to form a 5-membered or 6-membered ring optionally containing O, S, N(H) or N-alkyl; X is a bond or a divalent linking group selected from —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—, CH₂S—, —CH₂SCH₂—, —C(O)NH—, —C(O)N(R₇)—, —NHC(O)—, —N(R₇)C(O)—, —S(O)—, —S(O₂)—, —S(O)₂N(H)—, —S(O)₂N(R₇)—, —N(H)S(O)₂—, —N(R₇)S(O)₂— wherein the point of attachment of divalent linking groups, X, to R₃ in the Formulas I and II is to the right; Y is a bond or a divalent linking group selected from —O—, —OCH₂—, —OCH(R₇), —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—, CH₂S—, —CH₂SCH₂—, —C(O)NH—, —C(O)N(R₇)—, —NHC(O)—, —N(R₇)C(O)—, —S(O)—, —S(O₂)—, —S(O)₂N(H)—, —S(O)₂N(R₇)—, —N(H)S(O)₂—, —N(R₇)S(O)₂— wherein the point of attachment of divalent linking groups, Y, to R₄ in the Formulas I and II is to the right;

R₃ is (a) C₁-C₇ alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, and —S(O)₂— groups,

(b) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl,

(c) heterocycloalkylalkyl, or

(d) a group Z, wherein Z is a mono- or bi-cyclic ring system having 3 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH, C₁-C₄ alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. In the case where R₃ is a mono- or bi-cyclic ring system having 5 to 10 ring atoms, the attachment site may be either at a carbon atom or a nitrogen atom of the mono- or bi-cyclic ring system provided that only three bonds are made to nitrogen;

R₄ is a (a) C₁-C₇ alkyl group optionally and independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)₂— groups,

(b) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl,

(c) heterocycloalkylalkyl or

(d) a group Z, wherein Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH, C₁-C₄ alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. In the case where R₄ is a mono- or bi-cyclic ring system having 5 to 10 ring atoms, the attachment site may be either at a carbon atom or a nitrogen atom of the mono- or bi-cyclic ring system provided that only three bonds are made to nitrogen; and

R₅ is selected from: NO₂, NH₂, aryl, heteroaryl, F, Cl, Br, CN, OH, C₁-C₄ alkoxy, SR₆, S(O)₂R₆, S(O)₂N(R₇)₂, (C₁-C₄)alkyl, (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, —O—(C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, and (C₂-C₄)alkynyl, wherein each alkyl or cycloalkyl is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl provided that one or both of R₃ and R₄ is Z.

In one embodiment R₁ and R₂ are taken together form a 3-7 membered cycloalkyl or heterocycloalkyl ring. In another embodiment R₁ is hydrogen and R₂ is F, R₆, OH, OR₆, SR₆, NHR₇, N(R₇)₂ NHC(O)R₆, NHCO₂R₆ wherein R₆ and R₇ are as defined previously. In a further embodiment R₁ is hydrogen and R₂ is R₆, OR₆ or SR₆. In an additional embodiment R₁ is hydrogen and R₂ is alkyl, alkoxy or thioalkyl. In another embodiment R₁ is hydrogen and R₂ is R₆. In a further embodiment R₁ is hydrogen and R₂ is C1-C4 alkyl.

In one embodiment X is a bond. In another embodiment X is a divalent linking group selected from —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂₋₅ CH₂S—, —CH₂SCH₂₋₅—C(O)NH—, —C(O)N(R₇)—, —NHC(O)—, —N(R₇)C(O)—, —S(O)—, —S(O₂)—, —S(O)₂N(H)—, —S(O)₂N(R₇)—, —N(H)S(O)₂—, —N(R₇)S(O)₂— wherein the point of attachment of divalent linking groups, X, to R₃ in the Formulas I and II is to the right. In another embodiment X is —O—, —OCH₂—, —OCH(R₇)—, CH₂O—, —S—, —S(O)₂—, —S(O)₂N(H)—, —S(O)₂N(R₇)—, —C(O)NH— or —C(O)N(R₇)—. In a further embodiment X is —O—, —S(O)₂—, —S(O)₂N(H)— or —S(O)₂N(R₇)—. In another embodiment X is —O— or —S(O)₂—.

In one embodiment Y is a bond. In another embodiment Y is a divalent linking group selected from —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—, CH₂S—, —CH₂SCH₂—, —C(O)NH—, —C(O)N(R₇)—, —NHC(O)—, —N(R₇)C(O)—, —S(O)—, —S(O₂)—, —S(O)₂N(H)—, —S(O)₂N(R₇)—, —N(H)S(O)₂—, —N(R₇)S(O)₂— wherein the point of attachment of divalent linking groups, X, to R₃ in the Formulas I and II is to the right. In another embodiment Y is —O—, —OCH₂—, —OCH(R₇)—CH₂O—, —S—, —S(O)₂—, —S(O)₂N(H)—, —S(O)₂N(R₇)—, —C(O)NH— or —C(O)N(R₇)—. In a further embodiment Y is —O—, —S(O)₂—, —S(O)₂N(H)— or —S(O)₂N(R₇)—. In another embodiment Y is —O— or —S(O)₂—.

In one embodiment R₃ is a C1-C7 alkyl group optionally interrupted by —O—, —S—, —S(O)—, or —S(O)₂— groups. In another embodiment R₃ is a C1-C7 alkyl group. In a further embodiment R₃ is a C1-C4 alkyl group examples include but are not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl. In another embodiment R₃ is a cycloalkylalkyl group with examples including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. In another embodiment R₃ is heterocycloalkylalkyl. In another embodiment R₃ is a group Z as defined above wherein Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR_(E). In the latter embodiment Z comprises mono- or bi-cyclic ring system ring systems that furthermore may be fully saturated, partially saturated or aromatic. Examples of monocyclic ring systems that are fully saturated include but are not limited to 5-6 membered ring systems such as cyclohexyl, cyclopentanyl, piperazinyl, tetrahydrofuranyl and piperidinyl. Examples of monocyclic ring systems that are partially saturated include but are not limited to 5-6 membered ring systems such as cyclohexenyl, cyclopentenyl, dihydrofuranyl and tetrahydropyridinyl. piperidinyl. Examples of monocyclic ring systems that are aromatic include but are not limited to 5-6 membered ring systems such as phenyl, pyridyl, pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl, thiadizolyl, triazolyl, oxazolyl and thiazolyl. Examples of bicyclic ring systems that are fully saturated include but are not limited to 9-10 membered bicyclic ring systems such as decalinyl, decahydroquinolinyl and decahydroisoquinolinyl. Examples of bicyclic ring systems that are partially saturated include but are not limited to 9-10 membered bicyclic ring systems such as tetrahydronapthyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Examples of bicyclic ring systems that are aromatic include but are not limited to 9-10 membered bicyclic ring systems such as napthyl, indolyl, indazolyl, benzimidazolyl, benzthiadiazolyl and imidazopyridinyl. In one further embodiment the mono- or bi-cyclic ring system ring system comprises up to 2 nitrogen atoms and up to 1 sulfur or oxygen atoms.

In one embodiment R₄ is a C1-C7 alkyl group optionally interrupted by —O—, —S—, —S(O)—, or —S(O)₂— groups. In another embodiment R₄ is a C1-C7 alkyl group. In a further embodiment R₄ is a C1-C4 alkyl group examples include but are not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl. In another embodiment R₄ is a cycloalkylalkyl group with examples including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. In another embodiment R₄ is heterocycloalkylalkyl. In another embodiment R₄ is a group Z as defined above wherein Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR_(E). In the latter embodiment Z comprises mono- or bi-cyclic ring system ring systems that furthermore may be fully saturated, partially saturated or aromatic. Examples of monocyclic ring systems that are fully saturated include but are not limited to 5-6 membered ring systems such as cyclohexyl, cyclopentanyl, piperazinyl, tetrahydrofuranyl and piperidinyl. Examples of monocyclic ring systems that are partially saturated include but are not limited to 5-6 membered ring systems such as cyclohexenyl, cyclopentenyl, dihydrofuranyl and tetrahydropyridinyl. piperidinyl. Examples of monocyclic ring systems that are aromatic include but are not limited to 5-6 membered ring systems such as phenyl, pyridyl, pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl, thiadizolyl, triazolyl, oxazolyl and thiazolyl. Examples of bicyclic ring systems that are fully saturated include but are not limited to 9-10 membered bicyclic ring systems such as decalinyl, decahydroquinolinyl and decahydroisoquinolinyl. Examples of bicyclic ring systems that are partially saturated include but are not limited to 9-10 membered bicyclic ring systems such as tetrahydronapthyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Examples of bicyclic ring systems that are aromatic include but are not limited to 9-10 membered bicyclic ring systems such as napthyl, indolyl, indazolyl, benzimidazolyl, benzthiadiazolyl and imidazopyridinyl. In one further embodiment the mono- or bi-cyclic ring system ring system comprises up to 2 nitrogen atoms and up to 1 sulfur or oxygen atoms.

Other embodiments include compounds of Formulas III, IV, V, and VI and pharmaceutically acceptable salts thereof wherein R₁, R₂, R₃, R₄, R₅, X, Y and Z are as defined above.

Other embodiments include compounds of Formulas VII, VIII, IX, and X and pharmaceutically acceptable salts thereof wherein R₁, R₂, R₃, R₄, R₅, X, Y and Z are as defined above.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₂, R₃, R₄, R₅, X, Y and Z are as defined above and R₁ is hydrogen. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₃, R₄, R₅ and Z are as defined above; R₁ is hydrogen and R₂ is C₁-C₄ alkyl.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above and X and Y are independently chosen from a bond, —O—, —OCH₂—, —C(O)—, —S—, —S(O)₂—, —S(O)₂N(R₇)— and —N(R₇)S(O)₂—. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above and X and Y are independently chosen from a bond, —O—, —S(O)₂— and —S(O)₂N(R₇). Another embodiment comprises compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above and X and Y are independently chosen from a bond, —O— and S(O)₂N(R₇). A further embodiment comprises compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄, R₅, and Z are as defined above and X and Y are independently chosen from a bond and —O—.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₅, X, Y and Z are as defined above and R₃ and R₄ and are independently chosen from a C1-C7 alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, and —S(O)₂— groups, cycloalkylalkyl and heterocycloalkylalkyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₅, X, Y and Z are as defined above and R₃ and R₄ and are independently chosen from C₁-C₄ alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₅, Z are as defined above and X, Y and are independently chosen from a bond, —S—, —SO₂— and —O— and R₃ and R₄ and are independently chosen from C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₅, X, Y and Z are as defined above and R₃ and R₄ and are independently chosen from a group Z wherein Z is as defined above.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ and R₅, X and Y are as defined above and Z is a phenyl ring bearing up to 3 substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH, C₁-C₄ alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ and R₅, X and Y are as defined above, and Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH, C₁-C₄ alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ X, Y and Z are as defined above and R₅ is NO₂, NH₂, F, Cl, Br, CN, OH, C1-C4 alkoxy, SR₆, S(O)₂R₆ or S(O)₂N(R₇)₂. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ X, Y and Z are as defined above and R₅ is aryl or heteroaryl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ X, Y and Z are as defined above and R₅ is chlorine or fluorine.

Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₂, R₃, R₄, R₅, X, Y and Z are as defined above and R₁ is hydrogen. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₃, R₄, R₅ and Z are as defined above; R₁ is hydrogen and R₂ is C₁-C₄ alkyl.

Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above and X and Y are independently chosen from a bond, —O—, —OCH₂—, —C(O)—, —S—, —S(O)₂—, —S(O)₂N(R₇)— and —N(R₇)S(O)₂—. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above and X and Y are independently chosen from a bond, —O—, —S(O)₂— and —S(O)₂N(R₇). Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above and X and Y are independently chosen from a bond, —O— and S(O)₂N(R₇). Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above and X and Y are independently chosen from a bond and —O—.

Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₅, X, Y and Z are as defined above and R₃ and R₄ and are independently chosen from a C1-C7 alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, and —S(O)₂— groups, cycloalkylalkyl and heterocycloalkylalkyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₅, X, Y and Z are as defined above and R₃ and R₄ and are independently chosen from C₁-C₄ alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₅, Z are as defined above and X, Y and are independently chosen from a bond, —S—, —SO₂— and —O— and R₃ and R₄ and are independently chosen from C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₅, X, Y and Z are as defined above and R₃ and R₄ and are independently chosen from a group Z wherein Z is as defined above.

Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₃, R₄ and R₅, X and Y are as defined above and Z is a phenyl ring bearing up to 3 substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH, C₁-C₄ alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₃, R₄ and R₅, X and Y are as defined above, and Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing ring bearing up to 3 substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH, C₁-C₄ alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR_(E).

Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₄ X, Y and Z are as defined above and R₅ is NO₂, NH₂, F, Cl, Br, CN, OH, C1-C4 alkoxy, SR₆, S(O)₂R₆ or S(O)₂N(R₇)₂. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₄ X, Y and Z are as defined above and R₅ is aryl or heteroaryl. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₄ X, Y and Z are as defined above and R₅ is chlorine or fluorine.

The compounds of formulas I-IX are expected to alter the activity of γ-secretase and are expected to be useful for the treatment of Alzheimer's disease and other neurodegenerative disorders.

In another embodiment A is CO₂H.

In another embodiment a compound of formula (I) is selected.

In another embodiment a compound of formula (II) is selected.

In another embodiment a compound of formula (III) is selected.

In another embodiment a compound of formula (IV) is selected.

In another embodiment a compound of formula (V) is selected.

In another embodiment a compound of formula (VI) is selected.

In another embodiment a compound of formula (VII) is selected.

In another embodiment a compound of formula (VIII) is selected.

In another embodiment a compound of formula (IX) is selected.

In another embodiment R₁ and R₂ are independently selected from: H, (C₁-C₆)alkyl, (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, C₁-C₆ alkyl that is independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)₂— groups or heterocycloalkylalkyl wherein each alkyl or cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, oxo, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not H simultaneously or

R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which are; optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl or R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl ring substituted with R₂₀ and R₂₁ where R₂₀ and R₂₁ are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are independently selected from: H, (C₁-C₆)alkyl, (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl wherein each alkyl or cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ and R₂ are independently selected from: H, (C₁-C₆)alkyl, wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ and R₂ are independently selected from: H, (C₃-C₆)alkyl, wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ and R₂ are independently selected from: H, n-propyl, iso-propyl, iso-butyl, n-butyl, iso-pentyl, and n-pentyl wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ is H.

In another embodiment R₁ is H and R₂ is n-propyl.

In another embodiment R₁ is H and R₂ is iso-butyl.

In another embodiment R₁ is H and R₂ is n-butyl.

In another embodiment R₁ is H and R₂ is iso-pentyl.

In another embodiment R₁ is H and R₂ is n-pentyl.

In another embodiment R₁ and R₂ are independently selected from: H, (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl wherein cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ and R₂ are independently selected from: H, (C₀-C₁)alkyl-(C₃-C₇)cycloalkyl wherein cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ and R₂ are independently selected from: H, (C₀-C₁)alkyl-(C₃-C₅)cycloalkyl wherein cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ is H and R₂ is selected from cyclopentyl, cyclopropylmethyl and cyclobutylmethyl.

In another embodiment R₁ is H and R₂ is cyclopentyl.

In another embodiment R₁ is H and R₂ is cyclopropylmethyl.

In another embodiment R₁ is H and R₂ is cyclobutylmethyl.

In another embodiment R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which are; optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl

or R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl ring substituted with R₂₀ and R₂₁ where R₂₀ and R₂₁ are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which are; optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl ring which are; optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form a cyclopropyl ring.

In another embodiment R₁ and R₂ are taken together to form a cyclobutyl ring.

In another embodiment R₁ and R₂ are taken together to form a cyclopentyl ring.

In another embodiment R₁ and R₂ are taken together to form a cyclohexyl ring.

In another embodiment R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl ring substituted with R₂₀ and R₂₁ where R₂₀ and R₂₁ are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl ring substituted on the same carbon atom with R₂₀ and R₂₁ where R₂₀ and R₂₁ are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form a spiro[2.3]hexane, a spiro[3.3]heptane or a spiro[3.4]octane ring system.

In another embodiment R₁ and R₂ are taken together to form a spiro[2.3]hexane ring system.

In another embodiment R₁ and R₂ are taken together to form a spiro[3.3]heptane ring system.

In another embodiment R₁ and R₂ are taken together to form a spiro[3.4]octane ring system.

In another embodiment R₁ and R₂ are taken together to form a 5,5-disubstituted spiro[2.3]hexane ring system.

In another embodiment R₁ and R₂ are taken together to form a 2,2-disubstituted spiro[3.3]heptane ring system.

In another embodiment R₁ and R₂ are taken together to form a 2,2-disubstituted spiro[3.4]octane ring system.

In another embodiment R₁ and R₂ are independently selected from: H, F, OH, OR₆, SR₆, NHR₇, N(R₇)₂ NHC(O)R₆ or NHCO₂R₆ provided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ and R₂ if not H are unsubstituted, except that when R₁ and R₂ are taken with the carbon to which they are attached form C₃-C₇ ring, the ring may be substituted with R₂₀ and R₂₁, which themselves are unsubstituted. In another embodiment R₁ and R₂ if not H are optionally singly or multiply independently substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl In another embodiment R₁ and R₂ if not H are singly or multiply independently substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl

In another embodiment R₆ is C₁-C₆ alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)₂— groups, (C₃-C₇)cycloalkyl, (C₄-C₈) cycloalkylalkyl, heterocycloalkylalkyl.

In another embodiment R₆ is C₁-C₆ alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)₂— groups.

In another embodiment R₆ (C₃-C₇)cycloalkyl.

In another embodiment R₆ is a (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl

In another embodiment R₆ heterocycloalkylalkyl.

In another embodiment R₆ is (CH₂)_(n)Q.

In another embodiment R₆ is —CH₂-Q.

In another embodiment Q is aryl.

In another embodiment Q is heteroaryl.

In another embodiment Q is monocyclic heteroaryl.

In another embodiment Q is bicyclic heteroaryl.

In another embodiment X is a bond or a divalent linking group selected from —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—, CH₂S— or —CH₂SCH₂—.

In another embodiment X is a bond or a divalent linking group selected from —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂O—, —CH₂OCH₂— or —CH₂CH₂O.

In another embodiment X is a bond or a divalent linking group selected from —CH₂—, —C(O)—, —CH═CH— or —CH₂CH₂

In another embodiment X is a bond or a divalent linking group selected from —S—, —SCH₂₋₅ CH₂S— or —CH₂SCH₂—.

In another embodiment X is a bond or a divalent linking group selected from —O— or —S—.

In another embodiment X is a bond.

In another embodiment X is the divalent linking group —O—.

In another embodiment X is the divalent linking group —S—.

In another embodiment Y is a bond or a divalent linking group selected from —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂₋₅ CH₂S— or —CH₂SCH₂—.

In another embodiment Y is a bond or a divalent linking group selected from —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂O—, —CH₂OCH₂— or —CH₂CH₂O

In another embodiment Y is a bond or a divalent linking group selected from —CH₂—, —C(O)—, —CH═CH— or —CH₂CH₂—.

In another embodiment Y is a bond or a divalent linking group selected from —S—, —SCH₂—, CH₂S— or —CH₂SCH₂—.

In another embodiment Y is a bond or a divalent linking group selected from —O— or —S—.

In another embodiment Y is a bond.

In another embodiment Y is the divalent linking group —O—.

In another embodiment Y is the divalent linking group —S—.

In another embodiment R₃ is a C₁-C₄ alkyl group.

In another embodiment R₃ is a C₁-C₃ alkyl group.

In another embodiment R₃ is a C₂-C₃ alkyl group.

In another embodiment R₃ is selected from ethyl, n-propyl, iso-propyl, trifluoroethyl, or trifluoropropyl.

In another embodiment R₃ is ethyl.

In another embodiment R₃ is n-propyl.

In another embodiment R₃ is iso-propyl.

In another embodiment R₃ is trifluoroethyl.

In another embodiment R₃ is trifluoropropyl.

In another embodiment R₃ is a (C₄-C₁₀) cycloalkylalkyl group.

In another embodiment R₃ is a (C₀-C₃)alkyl-(C₃-C₇) cycloalkyl group.

In another embodiment R₃ is a (C₃-C₇) cycloalkyl group.

In another embodiment R₃ is a (C₁-C₃)alkyl-(C₃-C₇) cycloalkyl group.

In another embodiment R₃ is a (C₁)alkyl-(C₃-C₇) cycloalkyl group.

In another embodiment R₃ is a (C₁)alkyl-(C₃-C₄) cycloalkyl group.

In another embodiment R₃ is a cyclopropylmethyl group.

In another embodiment R₃ is a cyclobutylmethyl group.

In another embodiment R₃ is heterocycloalkylalkyl group.

In another embodiment R₃ is represented by the group Z.

In another embodiment R₃ is not cyclopropylmethyl

In another embodiment Z is monocyclic.

In another embodiment Z is bicyclic

In another embodiment Z is heteroaryl

In another embodiment Z is unsubstituted heteroaryl

In another embodiment Z is benzo[b]thiophenyl, benzo[c][1,2,5]oxadiazoyl,

benzo[c][1,2,5]thiadiazolyl or benzo[d]thiazolyl

In another embodiment Z is benzo[b]thiophenyl or benzo[d]thiazolyl

In another embodiment Z is benzo[c][1,2,5]oxadiazoyl or

benzo[c][1,2,5]thiadiazolyl

In another embodiment Z is benzo[b]thiophenyl

In another embodiment Z is benzo[c][1,2,5]oxadiazoyl

In another embodiment Z is benzo[c][1,2,5]thiadiazolyl

In another embodiment Z is benzo[d]thiazolyl

In another embodiment Z is aryl

In another embodiment Z is substituted phenyl

In another embodiment Z is 4-substituted phenyl

-   -   In another embodiment Z is optionally substituted with up to 3         substituents independently selected from halogen, R₆, CF₃, CN,         NO₂, OH, C₁-C₄ alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃,         OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆,         S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆,         NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂,         C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆ or COR₆ In another         embodiment Z is optionally substituted with up to 3 substituents         independently selected from halogen, R₆, CF₃, CN, NO₂, C₁-C₄         alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆,         SR₆, NHR₇, N(R₇)₂CO₂H, CO₂R₆ or COR₆     -   In another embodiment Z is optionally substituted with up to 3         substituents independently selected from halogen, R₆, CF₃, CN,         NO₂, C₁-C₄ alkoxy, aryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆ or         SR₆     -   In another embodiment Z is optionally substituted with up to 3         substituents independently selected from halogen, R₆, CF₃, CN,         NO₂, C₁-C₄ alkoxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆ or SR₆     -   In another embodiment Z is optionally substituted with up to 3         substituents independently selected from halogen, C₁-C₆ alkyl,         (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, CF₃, C₁-C₄ alkoxy, or SR₆     -   In another embodiment Z is optionally substituted with up to 3         substituents independently selected from F, Cl, C₁-C₃ alkyl,         (C₃-C₆)cycloalkyl, CF₃, C₁-C₄ alkoxy, S—(C₁-C₄)alkyl or         S—(C₀-C₃)alkyl-(C₃-C₇)cycloalkyl     -   In another embodiment Z is optionally substituted with up to 3         substituents independently selected from F, Cl, C₁-C₃ alkyl,         (C₃-C₆)cycloalkyl, CF₃, C₁-C₄ alkoxy, or S—(C₁-C₃)alkyl     -   In another embodiment Z is substituted CF₃, OCF₃, OCH₂CF₃, F,         Cl, SMe, Me, Et, iPr

In another embodiment Z is substituted with F

In another embodiment Z is substituted with Cl

In another embodiment Z is substituted with C₁-C₃ alkyl

In another embodiment Z is substituted with (C₃-C₆)cycloalkyl

In another embodiment Z is substituted with CF₃,

In another embodiment Z is substituted with C₁-C₄ alkoxy

In another embodiment Z is substituted with S—(C₁-C₃)alkyl

In another embodiment R₄ is a C₁-C₇ alkyl group.

In another embodiment R₄ is a C₁-C₄ alkyl group.

In another embodiment R₄ is a C₁-C₃ alkyl group.

In another embodiment R₄ is a C₂-C₃ alkyl group.

In another embodiment R₄ is selected from ethyl, n-propyl, iso-propyl, trifluoroethyl, or trifluoropropyl.

In another embodiment R₄ is ethyl.

In another embodiment R₄ is n-propyl.

In another embodiment R₄ is iso-propyl.

In another embodiment R₄ is trifluoroethyl.

In another embodiment R₄ is trifluoropropyl.

In another embodiment R₄ is a (C₄-C₁₀) cycloalkylalkyl group.

In another embodiment R₄ is a (C₀-C₃)alkyl-(C₃-C₇) cycloalkyl group.

In another embodiment R₄ is a (C₃-C₇) cycloalkyl group.

In another embodiment R₄ is a (C₁-C₃)alkyl-(C₃-C₇) cycloalkyl group.

In another embodiment R₄ is a (C₁)alkyl-(C₃-C₇) cycloalkyl group.

In another embodiment R₄ is a (C₁)alkyl-(C₃-C₄) cycloalkyl group.

In another embodiment R₄ is a cyclopropylmethyl group.

In another embodiment R₄ is a cyclobutylmethyl group.

In another embodiment R₄ is heterocycloalkylalkyl group.

In another embodiment R₄ is represented by the group Z.

In another embodiment R₄ is not cyclopropylmethyl

In another embodiment R₅ is, F, Cl, Br, CN, C₁-C₄ alkoxy, SR₆, (C₁-C₄) alkyl, (C₀-C₃)alkyl-(C₃-C₇) cycloalkyl, —(C₃-C₇) cycloalkly or (C₂-C₄) alkynyl, where each alkyl or cycloalkly is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₅ is, F, Cl, Br, CN, C₁-C₄ alkoxy, SR₆, (C₁-C₄) alkyl, (C₀-C₃)alkyl-(C₃-C₇) cycloalkyl, —(C₃-C₇) cycloalkly or (C₂-C₄) alkynyl, where each alkyl or cycloalkly is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₅ is F, Cl, Br, CN, C₁-C₄ alkoxy, —S—(C₁-C₄)alkyl or (C₁-C₄) alkyl, where each alkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₅ is F, Cl, Br, CN, C₁-C₃ alkoxy —S—(C₁-C₃)alkyl or (C₁-C₃) alkyl, where each alkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₅ is F, Cl, Br or CN.

In another embodiment R₅ is F or Cl.

In another embodiment R₅ is F.

In another embodiment R₅ is Cl.

In another embodiment R₅ is Br.

In another embodiment R₅ is CN.

In another embodiment R₅ is C₁-C₃ alkoxy —S—(C₁-C₃)alkyl or (C₁-C₃) alkyl.

In another embodiment R₅ is C₁-C₃ alkoxy.

In another embodiment R₅ is tri-fluoroethoxy or tri-fluoropropoxy.

In another embodiment R₅ is (C₁-C₃) alkyl.

In another embodiment R₅ is CF₃.

In another embodiment R₅ is —S—(C₁-C₃)alkyl.

In another embodiment R₅ is —S-Me, —S-Et or —S—CH₂CF₃.

In another embodiment R₅ is SR₆.

In another embodiment R₅ is (C₀-C₃)alkyl-(C₃-C₇) cycloalkyl, (C₂-C₄) alkynyl, or —(C₃-C₇) cycloalkyl.

In another embodiment R₅ is (C₀-C₃)alkyl-(C₃-C₇) cycloalkyl.

In another embodiment R₅ is (C₂-C₄) alkynyl.

In another embodiment R₅ is trifluoroethynyl.

In another embodiment R₅ is (C₃-C₇) cycloalkyl.

In another embodiment R₅ is cyclopropyl.

In another embodiment R₅ is NO₂ or NH₂.

In another embodiment R₅ is aryl or heteroaryl.

In another embodiment the compound is a compound selected from examples 100-3217.

In another embodiment a racemic compound described in the disclosure is selected. In another embodiment a single enantiomer of the previous embodiments is selected. In another embodiment a single enantiomer of configuration (R) of the previous embodiments is selected. In another embodiment a single enantiomer of configuration (S) of the previous embodiments is selected. In another embodiment a solvate of a compound of formula (I-IX) is selected. In another embodiment a polymorph of compound of formula (I-IX) is selected. In a separate embodiment, a pharmaceutical composition comprising of the compound of the previous embodiments and a pharmaceutically acceptable carrier.

In a separate embodiment, a method for treating a neurodegenerative disorder comprising administering to a patient an effective amount of the pharmaceutical composition of the previous embodiments.

In another embodiment a method for treating Alzheimer's Disease comprising administering to a patient an effective amount of the pharmaceutical composition of the previous embodiments.

In the case compounds of Formula (I-IX) may contain asymmetric centers and exist as different enantiomers or diastereomers. All enantiomers or diastereomeric forms are embodied herein.

Compounds in the disclosure, e.g., compounds of Formulas I-IX, may be in the form of pharmaceutically acceptable salts. The phrase “pharmaceutically acceptable” refers to salts prepared from pharmaceutically acceptable non-toxic bases and acids, including inorganic and organic bases and inorganic and organic acids. Salts derived from inorganic bases include lithium, sodium, potassium, magnesium, calcium and zinc. Salts derived from organic bases include ammonia, primary (e.g. Tromethamine), secondary and tertiary amines, and amino acids (e.g. Lysine). Salts derived from inorganic acids include sulfuric, hydrochloric, phosphoric, methanesulphonic, hydrobromic. Salts derived from organic acids include C₁₋₆ alkyl carboxylic acids, di-carboxylic acids and tricarboxylic acids such as acetic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid, and alkylsulfonic acids such as methanesulphonic, and aryl sulfonic acids such as para-tolouene sulfonic acid and benzene sulfonic acid. For detailed list of slats see P. H. Stahl and C. G. Wermuth (eds.) “Handbook of Pharmaceutical Salts, Properties, Selection and Use” Wiley-VCH (ISBN 3-906390-26-8)

Compounds and pharmaceutically acceptable salts thereof may be in the form of a solvates. This occurs when a compound of formula (I-IX)) crystallizes in a manner that it incorporates solvent molecules into the crystal lattice. Examples of solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone. Formulas I-IX cover all solvates of the depicted compounds.

Compounds in the disclosure may exist in different crystal forms known as polymorphs.

Practitioners of the art will recognize that certain chemical groups may exist in multiple tautomeric forms. The scope of this disclosure is meant to include all such tautomeric forms. For example, a tetrazole may exist in two tautomeric forms, 1-H tetrazole and a 2-H tetrazole. This is depicted in FIGURE below. This example is not meant to be limiting in the scope of tautomeric forms.

Practitioners of the art will recognize that certain electrophilic ketones, may exist in a hydrated form. The scope of this disclosure is to include all such hydrated forms. For example, a trifluoromethyl ketone may exist in a hydrated form via addition of water to the carbonyl group. This is depicted in FIGURE below. This example is not meant to be limiting in the scope of hydrated forms.

Abbreviations used in the following examples and preparations include:

-   -   Aβ Amyloid-beta     -   ABL Aβ lowering     -   Ac acyl (Me-C(O)—)     -   AD Alzheimer's Disease     -   APP Amyloid Precursor Protein     -   Bn Benzyl     -   b/p brain/plasma     -   BSA Bovine serum Albumin     -   c Cyclo     -   calcd. Calculated     -   cBu Cylcobutyl     -   c-Bu Cylcobutyl     -   c_(max) Maximal concentration     -   cPr Cyclopropyl     -   c-Pr Cyclopropyl     -   CHAPS 3-[3-cholamidopropyl)-dimethyl-ammonio]-1-propane         sulfonate     -   CTF Carboxy Terminal Fragment     -   CSF Cerebrospinal fluid     -   DAPT         N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl         ester     -   DCC N,N′, Dicyclohexylcarbodiimide     -   DEA Di-ethylamine     -   DIEA Di-isopropylethyl amine     -   DMAP 4-Dimethylamino Pyridine     -   DMF Dimethylformamide     -   DMSO Dimethyl sulfoxide     -   Dppf 1,4-Bis(diphenylphosphino) ferrocene     -   EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride     -   EDTA Ethylene Diamine Tetra-acetic Acid     -   ELISA Enzyme-Linked Immuno Sorbent Assay     -   Et₃N Triethylamine     -   Eq. Equivalent     -   g gram(s)     -   HOBt 1-Hydroxybenzotriazole     -   HPLC High Pressure Liquid Chromatography     -   h Hour(s)     -   hr Hour(s)     -   i.v or IV. Intravenous     -   KHMDS Potassium Hexamethydisilazide     -   LC-MS Liquid Chromatography-Mass Spectrometry     -   LDA Lithium Di-isopropylamide     -   m Multiplet     -   MeOH Methyl Alcohol or Methanol     -   m meta     -   mcpba meta-chloro perbenzoic acid     -   min Minute(s)     -   mmol millimoles     -   mmole millimoles     -   ul Microliter     -   μl microliter     -   Ms Mesylate     -   MS Mass Spectrometry     -   MW Molecular Weight (all values are ±0.05)     -   n normal     -   NBS N-Bromosuccinimide     -   NCS N-Chlorosuccinimide     -   NIS N-Iodosuccinimide     -   NMR Nuclear Magnetic Resonance     -   NMM N-Methyl Morpholine     -   NSAIDS Non-Steroidal Anti-Inflammatory Drugs     -   o ortho     -   o/n overnight     -   p para     -   PBS Phosphate Buffered Saline     -   PEPPSI         1,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)         palladium(II) dichloride     -   PhNTf₂         1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide     -   POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp)         palladate (2-)     -   p.s.i. Pounds per square inch     -   PPAA 1-Propanephosphonic Acid Cyclic Anhydride     -   PyBOP® Benzotriazol-1-yl-oxytripyrrolidinophosphonium         hexafluorophosphate     -   PK Pharmacokinetics     -   RT (or rt) room temperature (about 20-25° C.)     -   s Singlet     -   sat. Saturated     -   sec secondary     -   t Triplet     -   tert tertiary     -   TBAF Tetra-butyl ammonium fluoride     -   TFA Trifluoroacetic Acid     -   THF Tetrahydrofuran     -   TMB 3,3′ 5, 5′ Tetramethylbenzidine     -   TMS Trimethylsilyl     -   Tf Triflate     -   Ts Tosylate     -   v/v volume/volume     -   wt/v weight/volume

DESCRIPTION OF THE FIGURE

FIG. 1 demonstrates the desirable effect on Aβ after the administration of example 1301 (2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid) to in C57BL/6 mice when give one dose at 30 mg/kg in a Solutol HS 15: Ethanol:Water (15:10:75) formulation (measuring Aβ at 3 hours).

DETAILED DESCRIPTION

Described below are compounds within Formulas I and II as well as methods for preparing the compounds and using the compounds to treat one or more symptoms of Alzheimer's disease. The compounds of the disclosure are gamma secretase modulators (GSMs), i.e., compounds that act to shift the relative levels of Aβ peptides produced by γ-secretase. In some cases the compounds alter the relative levels of Aβ peptides produced by γ-secretase without significantly changing the total level of Aβ peptides produced.

General Reaction Schemes

The tetrasubstituted benzene compounds of Formulas I and II may be prepared by multistep organic synthetic routes from known fluoronitrobenzene and chloronitrobenzene starting materials e.g. 2,4-difluoronitrobenzene, 4-fluoro-2-cyano-nitrobenzene, 3-nitro-4-chlorobenzene, 2,4,5-trifluoronitrobenzene, 2,4,5-trichloronitrobenzene or alternatively from 4-hydroxyphenyl and 4-aminophenyl acetic acid starting materials by one skilled in the art of organic synthesis using established organic synthesis procedures.

The 1-position acetic acid moiety common to compounds of Formulas I and II, as the free acid itself or as an ester derivative thereof, is already present in the case of a 4-hydroxyphenyl acetic acid or 4-hydroxyphenyl acetic acid ester starting material. In the case of a 4-fluoronitrobenzene starting materials or intermediates, the acetic acid moiety can be introduced by standard nucleophilic aromatic substitution of the 4-fluoro group with an unsubstituted malonic ester (eg diethyl malonate) or a malonic ester derivative already bearing an R₁ group (eg. diethyl 2-isobutylmalonate). Introduction of the X—R₃ and Y—R₄ groups or intermediate groups that are further elaborated to X—R₃ and Y—R₄ can be carried out by substitution or manipulation of suitable 3 or 4-position functional groups in appropriate starting materials or intermediates en route to Formulas I and II respectively. In cases where X or Y is a bond, a 3 or 4-position halogen or triflate group is replaced with an aryl or heteroaryl group by carbon-carbon bond forming reaction typically a Suzuki coupling reaction. In cases where X or Y is O, S or N, a 3 or 4-position halogen (eg the corresponding 2-fluoro group of a 2,4-difluoronitrobenzene starting material) substitution reaction is performed using HO—R₃ or HS—R₃ or H₂N—R₃ and a base (eg NaH, K₂CO₃) in a suitable solvent (eg DMF). Compounds where X or Y is —S(O)— or —S(O₂)— are prepared by oxidation of compounds where X or Y is S. Compounds where X or Y is —S(O)₂N(H)—, —S(O)₂N(R₅)— can be prepared by conversion of a 3 or 4-position nitro group (eg the nitro group of the nitrobenzene starting material) to a sulfonyl chloride via Sandmeyer reaction followed by addition of the corresponding amine. Compounds where X or Y is N(H)S(O)₂— or —N(R₅)S(O)₂— can be prepared by reduction of a 3 or 4-position nitro group to the corresponding aniline followed by reaction with the corresponding sulfonylchloride. Compounds where X or Y is NHC(O)— or —N(R₅)C(O)— can be prepared by reduction of a 3 or 4-position nitro group to the corresponding aniline followed by reaction with the corresponding carboxylic acid chloride. Compounds where X or Y is a —C(O)— can be prepared by addition of an organometallic reagent (e.g., a Grignard reagent or organolithium) to a 3 or 4-position cyano group directly or in a 2-step sequence by addition of an organometallic reagent to a 3 or 4-position carboxaldehyde group followed by oxidation. Compounds where X or Y is —C(O)NH— or C(O)N(R₅)—)— can be prepared by addition of a corresponding amine to a 3 or 4-position carboxylic acid which in turn may be prepared by hydrolysis of a 3 or 4-position cyano group. Either aromatic nucleophilic substitution of a 2-fluoro-1-nitrobenzene intermediate or alkylation of a 3 or 4-hydroxybenzene intermediate with the corresponding alkyl bromide or triflate may be used to prepare compounds of Formulas I and II where the R₄ group is OCH₂CF₃, C₂-C₄ alkoxy, or cyclopropyloxymethyl. Compounds wherein the R₄ group is an alkyl, aryl or heteroaryl group attached by a carbon-carbon bond may be prepared by a Suzuki coupling reaction. In this process an aryl or heteroaryl boronic acid or borate ester is reacted with an intermediate compound having a 3 or 4-position halogen or triflate group. This method results in replacement of the halogen or triflate group with an aryl or heteroaryl group which is then bonded to the intermediate at the carbon atom previously bearing the boronic acid or ester group. Compounds wherein the R₄ group is a heteroaryl group attached by a carbon-nitrogen bond may be prepared by reacting a 3 or 4-iodo intermediate with a heteroaromatic heterocycle having an acidic N—H group under Ulman reaction or copper catalyzed reaction conditions.

Compounds of Formulas I and II wherein A=tetrazole may be prepared from their corresponding nitriles A=CN which are available via dehydration of the corresponding primary amides A=CONH₂ whose preparation is described above. Thus, treatment of the nitrile with an azide, such as sodium azide or tributylstanyl azide (Bu₃SnN₃) at a temperature of 20-100° C., optionally with a solvent such as DMF, THF or DMSO.

Compounds of the disclosure of Formula III in which R₁ is R₈ an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, Y is O, X is a bond, R₃ is Z, R₄ and R₅ are as described previously and thus having general Formula XXIV may be prepared generally as depicted in Scheme 1.

Thus, as depicted in Scheme 1 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl or arylalkyl R₈ group is introduced in the first step by treating ethyl 4-benzyloxyphenylacetate one equivalent of a suitable deprotonating base such as sodium hydride in an appropriate organic solvent followed by the addition of the corresponding reactive alkyl bromide R₈Br such as isobutylbromide to yield XX where R₉ is hydrogen. In cases where a second alkyl or aralkyl group is present this alkylation step is repeated using R₉Br as an alkylating agent. In cases where a spirocyclic ring is formed by R₈ and R₉ (e.g. cyclopropyl) then the appropriate dibromide is used (e.g. dibromoethane in the case of cyclopropyl). The benzyl group is then removed under standard catalytic hydrogenation conditions and the resulting phenol is treated with bromine in acetic acid to give the bromophenol intermediate XXI. Nitration of XXI then yields nitrophenol intermediate XXII which then us subjected to a standard base mediated aliphatic or aromatic nucleophilic substitution reaction with an alkyl or aryl halide R₄—X to give intermediate XXIII where R₄ is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl. This is then followed by introduction of the Z group by standard reactions. Such reactions are exemplified by the well established Suzuki coupling of a substituted aryl or heteroaryl boronic acid derivative Z—B(OH)₂ using a suitable palladium(0) catalyst typically bearing with phosphine ligands (e.g. Pd(PPh₃)₄ or tetrakistriphenylphosphine) in the case where Z is linked by a carbon-carbon bond and by copper (eg CuI) mediated Ulman type coupling of a heteroaryl ring bearing an active N—H group where Z is a heteroaryl ring linked by a nitrogen-carbon bond.

After introduction of the Z group, the nitro group is converted to the corresponding aniline by any number of standard reduction conditions (eg SnCl₂ reduction). This is followed by conversion of the resulting aniline to the diazonium salt which is then converted “in situ” either directly to R₅ either directly in the case where R₅ is F, Cl, Br, CN, OH, C1-C4 alkoxy or SR₆, by using the appropriate copper salt ie CuCl, CuBr, CuCN or nucleophile ie water, alcohol or thiol or in a subsequent step e.g. oxidation (eg with MCPBA) of the product of thiol coupling when R₅ is S(O)₂R₆; e.g. Suzuki coupling of the bromide product when R₅ is heteroaryl e.g. treatment of an intermediate sulfonylchloride obtained via CuCl/SO₂ conditions with an amine HN(R₇)₂, when R₅ is S(O)₂N(R₇)₂, e.g. Burton trifluoromethylation reaction of the iodide product (Burton, D. J.; Wiemers, D. M. J. Am. Chem. Soc. 1985, 107, 5014 and 1986, 108, 832; Miller, J. A., Coleman, M. C.; Matthews, R. S. J. Org. Chem. 1993, 58, 2637) when R₅ is CF₃ Standard ester hydrolysis yields compounds of Formula XXIV.

Compounds of the disclosure of Formula III in which R₁ is OH, OR₆, SR₆, NHR₇, N(R₇)₂ NHC(O)R₆ or NHCO₂R₆; R₂ is H; Y is O, X is a bond, R₃ is Z, R₄ and R₅ are as described previously and thus having general Formula XXVII may be prepared generally as depicted in Scheme 2. Thus, as depicted in Scheme 2 bromination of intermediates of general Formula XXV, prepared according to Scheme 1, e.g. with N-bromosuccinimide (NBS) yields intermediate XXVI. In a subsequent step the Br atom is replaced by a suitable alkoxide, thiolate or masked amine nucleophile (eg azide or N₃). The product of the latter reaction is either directly subjected to ester hydrolysis or further processed in optional steps (eg by conversion the masked amine to an amino group followed by reductive amination to give mono or dialkylamine derivatives, and optionally acylation or carbamoylation of such amine derivatives) and then subjected to final ester hydrolysis to give compounds of Formula XXVII in which R₁₀ is OH, OR₆, SR₆, NHR₇, N(R₇)₂ NHC(O)R₆ or NHCO₂R₆

Compounds of the disclosure of Formula III and IV in which R₁ is R₈ an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, X and Y are a bond, R₃ and R₄ are respectively Z₁ and Z₂ representing independently chosen Z groups as defined above and R₅ is as described previously and thus having general Formula XXX may be prepared generally as depicted in Scheme 3 starting from compounds of general Formula XXII which can be prepared as described in Scheme 1.

Compounds of Formula V in which R₁ is R₈ an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is Q=O, S, or SO₂; R₅ is F or Cl; R₃ and Z are as described previously and thus having general Formula XXXIV may be prepared generally as depicted in Scheme 4. Accordingly, the 4-halo group of 2,4,5-trifluoronitrobenzene or 2,4,5-trichloronitrobenzene is selectively displaced by reaction with a 2-substituted diethylmalonate R₈YCH(CO₂Et)₂ under basic conditions (eg NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXI. Subsequently the 2-halo group undergoes nucleophilic aromatic substitution reaction by treatment with a R₃-J-H compound (wherein J is O, S) under basic conditions (eg NaH/DMF) followed by reduction and Sandmeyer reaction to give iodide XXXII.

Suzuki coupling then gives intermediates of general formula XXXIII. Introduction of an R₉ group may be conducted using alkylation conditions described above. Compounds wherein J is SO₂ may be prepared by standard oxidation of intermediates XXXIII wherein J is S. Final products having general Formula XXXIV are then prepared by standard ester hydrolysis.

Compounds of Formula IV in which R₁ is R₈ an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is O; R₅ is Cl; R₃ and Z are as described previously and thus having general Formula XXXVIII may be prepared generally as depicted in Scheme 5. Accordingly, the 4-fluoro group of 2,4-difluoronitrobenzene is selectively displaced by reaction with a 2-substituted diethylmalonate R₈CH₂(CO₂Et)₂ under basic conditions (eg NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXV. Subsequently the 2-halo group undergoes nucleophilic aromatic substitution reaction by treatment with a R₃—O—H compound under basic conditions (eg NaH/DMF) followed by reduction and chlorination reaction (eg with N-chlorosuccinimide) to give chloroaniline intermediates of general formula XXXVI. Sandmeyer iodination reaction to followed by Suzuki coupling then gives intermediates of general formula XXXVII. Introduction of an R₉ group may be conducted using alkylation conditions described above. Final products having general Formula XXXVIII are then prepared by standard ester hydrolysis.

Compounds of Formula IV in which R₁ is R₈ an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is J=O, S; R₅ is NO₂, NH₂, CN, SR₆, SO₂R₆, SO₂N(R₇)₂F, Cl, Br; R₃ and Z are as described previously and thus having general Formula XLII may be prepared generally as depicted in Scheme 6. Accordingly, the 2-fluoro group of 2,4-difluoronitrobenzene is selectively displaced by reaction with a an alcohol or thiol of formula R₃-J-H under basic conditions (eg NaH/DMF). The 4-fluoro group of the resulting product is substituted with diethylmalonate under basic conditions (eg NaH/DMF) followed by hydrolysis and esterification to give intermediates of Formula XXXIX. Reduction of the nitro group of XXXIX followed by nitration of the resulting aniline give nitroaniline intermediates of Formula XL. Sandmeyer iodination reaction, followed by Suzuki coupling and finally alkylation reaction to introduce R₈ then gives intermediates of general Formula XLI. The nitro group of XLI may be optionally reduced via any number of standard reduction conditions (eg SnCl₂) to an aniline which may in turn optionally be converted to diverse other R₅ groups either directly or in multistep procedures. Thus, in the case where R₅ is F, Cl, Br, CN, OH, C1-C4 alkoxy or SR₆, diazotization of the aniline is followed by direct “in situ” conversion to R₅ using the appropriate copper salt ie CuCl, CuBr, CuCN or nucleophile ie water, alcohol or thiol. Intermediates where R₅ is S(O)₂R₆ may be prepared by subsequent step oxidation (eg with MCPBA) of the above products of thiol coupling wherein R₅ is SR₆. Intermediates where R₅ is eg heteroaryl, C₂-C₄ alkynyl or cyclopropyl may be prepared by subsequent Suzuki coupling of the above products wherein R₅ is Br or I. Intermediates where R₅ is CF3 may be prepared by Burton reaction of the above products wherein R₅ is I. Intermediates where R₅ is S(O)₂N(R₇)₂, may be prepared by subsequent reaction of above direct sulfonylchloride products (obtained via CuCl/SO₂ conditions) with an amine HN(R₇)₂, Final products having general Formula XLII are then prepared by optional alkylation reaction to introduce R₉ followed by standard ester hydrolysis.

Compounds of Formula VII in which R₁ is R₈ an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is J=O, S; R₅ is NO₂, NH₂, CN, SR₆, SO₂R₆, SO₂N(R₇)₂F, Cl, Br; R₃ and Z are as described previously and thus having general Formula XLV may be prepared generally as depicted in Scheme 7. Reduction of the nitro group of XXXIX followed by bromination (eg with NBS) of the resulting aniline and prepared by 1 alkylation reaction to introduce R₉ gives bromoaniline intermediates of Formula XLIII Suzuki coupling reaction substitutes Z groups for the Br group to give intermediates of general Formula XLIV. The aniline group in intermediates of Formula XLIV may in turn optionally be converted to diverse other R₅ groups either directly or in multistep procedures. Thus, in the case where R₅ is F, Cl, Br, CN, OH, C1-C4 alkoxy or SR₆, diazotization of the aniline is followed by direct “in situ” conversion to R₅ using the appropriate copper salt ie CuCl, CuBr, CuCN or nucleophile ie water, alcohol or thiol. Intermediates where R₅ is S(O)₂R₆ may be prepared by subsequent step oxidation (eg with MCPBA) of the above products of thiol coupling wherein R₅ is SR₆. Intermediates where R₅ is eg heteroaryl, C2-C4 alkynyl or cyclopropyl may be prepared by subsequent Suzuki coupling of the above products wherein R₅ is Br or I. Intermediates where R₅ is CF3 may be prepared by Burton reaction of the above products wherein R₅ is I. Intermediates where R₅ is S(O)₂N(R₇)₂, may be prepared by subsequent reaction of above direct sulfonylchloride products (obtained via CuCl/SO₂ conditions) with an amine HN(R₇)₂, Final products having general Formula XLII are then prepared by optional alkylation reaction to introduce R₉ followed by standard ester hydrolysis.

Compounds of Formula IV in which R₁ is R₈ an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X—R₃ and R₅ are identical (J-R3 in Scheme 8) and are either C1-C4 alkoxy or SR₆ groups; and Z is as described previously and thus having general Formula L may be prepared generally as depicted in Scheme 8. Accordingly, the 2 and 6-fluoro groups of 2,4,6-trifluoronitrobenzene are selectively displaced by reaction with a an alcohol or thiol of formula R₃-J-H under basic conditions (eg NaH/DMF). The 4-fluoro group of the resulting product is substituted with diethylmalonate under basic conditions (eg NaH/DMF) followed by hydrolysis and esterification to give intermediates of Formula XLVIII. Reduction of the nitro group of followed by Sandmeyer iodination reaction of the resulting aniline gives intermediates of Formula XLVIII. Suzuki coupling and followed by alkylation reaction to introduce R₈ then gives intermediates of general Formula XLIX. Final products having general Formula L are then prepared by optional alkylation reaction to introduce R₉ followed by standard ester hydrolysis.

Enantioselective Methods

Compounds of formulas I-IX may be prepared in an enantioselectively, this can be accomplished via resolution via chiral HPLC(CHIRALPAK-AD H (250×4.6 mm, 5 μm). Mobile phase: Hexane (0.1% TFA):IPA (93:7), Flow rate 0.8 mL/min., Diluent Hexane:IPA (90:10); Column temperature 40° C.) or via asymmetric synthesis. The phenyl acetic acids of formula (XXXV) are converted into the corresponding acid chlorides, via treatment with SOCl₂ or oxalyl chloride with a catalytic amount of DMF. The reaction is performed in an inert solvent such as CH₂Cl₂, CHCl₃, THF, or toluene at a temperature of 0-80° C. The acid chloride is treated with either (R)- or (S)-4-benzyloxazolidin-2-one to (R isomer depicted-XXXXVI) give the oxazolidinone (XXXVII). The oxazolidinone ( ) is then subjected to a base such as NaHMDs, LiHMDS, KHMDS, BuLi or KO^(t)Bu in an inert solvent such as THF, Me-THF or Et₂O at a temperature of −78 to 0° C. The subsequent enolate is then treated with the appropriate electrophile to give the alkylated oxazolidinone (XXXVIII). The chiral auxillary is removed under conditions such as LiOH/H₂O₂ followed by a reductive work up with a reagent such as sodium bi-sulfite to give the desired products of formulas (I-IX).

Alternatively the racemic compound of formula (I-IX) may be coupled to the Evans chiral oxazolidinone via an intermediate such as the corresponding acid chloride. Upon completion of the coupling, the reaction produces a mixture of diastereoisomers which may be separated by methods such as flash chromatography or crystallization to give single diastereoisomers or enriched mixtures favoring one diastereoisomer over the other (see scheme 10). The auxillary may be removed as described previously.

Examples of enantiomers include but are not limited to;

-   (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic     acid compound -   (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic     acid -   (R)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic     acid -   (S)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic     acid -   (R)-4-methyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)pentanoic     acid -   (S)-4-methyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)pentanoic     acid -   (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (R)-4-methyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)pentanoic     acid -   (S)-4-methyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)pentanoic     acid -   (R)-3-cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)propanoic     acid -   (S)-3-cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)propanoic     acid -   (R)-3-cyclopropyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)propanoic     acid -   (S)-3-cyclopropyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)propanoic     acid -   (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic     acid -   (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic     acid -   (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (R)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic     acid -   (S)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic     acid -   (R)-3-cyclopropyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)propanoic     acid compound -   (S)-3-cyclopropyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)propanoic     acid compound -   (R)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (S)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic     acid -   (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic     acid -   (R)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (S)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic     acid -   (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic     acid -   (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic     acid -   (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic     acid -   (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic     acid -   (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic     acid -   (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic     acid -   (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic     acid -   (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic     acid -   (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic     acid -   (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic     acid -   (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic     acid -   (R)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic     acid -   (S)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic     acid -   (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic     acid -   (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic     acid -   (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic     acid -   (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic     acid -   (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic     acid -   (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic     acid -   (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (R)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic     acid -   (S)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic     acid -   (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (R)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (S)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic     acid -   (R)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (S)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic     acid -   (R)-4-methyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)pentanoic     acid -   (S)-4-methyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)pentanoic     acid

In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in Tables below.

TABLE 1 Formula III

Ex R1 R2 Y R4 R5 Z 100 CH3 H O CH2CH3 F 4-fluorophenyl 101 CH2CH3 H O CH2CH3 F 4-fluorophenyl 102 CH2CF3 H O CH2CH3 F 4-fluorophenyl 103 CH2CH2CH3 H O CH2CH3 F 4-fluorophenyl 104 CH2CH(CH3)2 H O CH2CH3 F 4-fluorophenyl 105 cyclopropylmethyl H O CH2CH3 F 4-fluorophenyl 106 SCH(CH3)2 H O CH2CH3 F 4-fluorophenyl 107 OCH2CH3 H O CH2CH3 F 4-fluorophenyl 108 (CH2)2 O CH2CH3 F 4-fluorophenyl 109 (CH2)4 O CH2CH3 F 4-fluorophenyl 110 CH3 H O CH2CH3 F 4-chlorophenyl 111 CH2CH3 H O CH2CH3 F 4-chlorophenyl 112 CH2CF3 H O CH2CH3 F 4-chlorophenyl 113 CH2CH2CH3 H O CH2CH3 F 4-chlorophenyl 114 CH2CH(CH3)2 H O CH2CH3 F 4-chlorophenyl 115 cyclopropylmethyl H O CH2CH3 F 4-chlorophenyl 116 SCH(CH3)2 H O CH2CH3 F 4-chlorophenyl 117 OCH2CH3 H O CH2CH3 F 4-chlorophenyl 118 (CH2)2 O CH2CH3 F 4-chlorophenyl 119 (CH2)4 O CH2CH3 F 4-chlorophenyl 120 CH3 H O CH2CH3 F 4-trifluoromethylphenyl 121 CH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 122 CH2CF3 H O CH2CH3 F 4-trifluoromethylphenyl 123 CH2CH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 124 CH2CH(CH3)2 H O CH2CH3 F 4-trifluoromethylphenyl 125 cyclopropylmethyl H O CH2CH3 F 4-trifluoromethylphenyl 126 SCH(CH3)2 H O CH2CH3 F 4-trifluoromethylphenyl 127 OCH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 128 (CH2)2 O CH2CH3 F 4-trifluoromethylphenyl 129 (CH2)4 O CH2CH3 F 4-trifluoromethylphenyl 130 CH3 H O CH2CH3 F 4-methoxyphenyl 131 CH2CH3 H O CH2CH3 F 4-methoxyphenyl 132 CH2CF3 H O CH2CH3 F 4-methoxyphenyl 133 CH2CH2CH3 H O CH2CH3 F 4-methoxyphenyl 134 CH2CH(CH3)2 H O CH2CH3 F 4-methoxyphenyl 135 cyclopropylmethyl H O CH2CH3 F 4-methoxyphenyl 136 SCH(CH3)2 H O CH2CH3 F 4-methoxyphenyl 137 OCH2CH3 H O CH2CH3 F 4-methoxyphenyl 138 (CH2)2 O CH2CH3 F 4-methoxyphenyl 139 (CH2)4 O CH2CH3 F 4-methoxyphenyl 140 CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 141 CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 142 CH₂CF₃ H O CH₂CH₃ F 3,4 dichloro phenyl 143 CH₂CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 144 CH₂CH(CH₃)₂ H O CH₂CH₃ F 3,4 dichloro phenyl 145 cyclopropylmethyl H O CH₂CH₃ F 3,4 dichloro phenyl 146 SCH(CH₃)₂ H O CH₂CH₃ F 3,4 dichloro phenyl 147 OCH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 148 (CH₂)₂ O CH₂CH₃ F 3,4 dichloro phenyl 149 (CH₂)₄ O CH₂CH₃ F 3,4 dichloro phenyl 150 CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 151 CH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 152 CH₂CF₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 153 CH₂CH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 154 CH₂CH(CH₃)₂ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 155 cyclopropylmethyl H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 156 SCH(CH₃)₂ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 157 OCH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 158 (CH₂)₂ O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 159 (CH₂)₄ O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 160 CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 161 CH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 162 CH₂CF₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 163 CH₂CH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 164 CH₂CH(CH₃)₂ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 165 cyclopropylmethyl H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 166 SCH(CH₃)₂ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 167 OCH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 168 (CH₂)₂ O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 169 (CH₂)₄ O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 170 CH₃ H O CH₂CF₃ F 4-fluorophenyl 171 CH₂CH₃ H O CH₂CF₃ F 4-fluorophenyl 172 CH₂CF₃ H O CH₂CF₃ F 4-fluorophenyl 173 CH₂CH₂CH₃ H O CH₂CF₃ F 4-fluorophenyl 174 CH₂CH(CH₃)₂ H O CH₂CF₃ F 4-fluorophenyl 175 cyclopropylmethyl H O CH₂CF₃ F 4-fluorophenyl 176 SCH(CH₃)₂ H O CH₂CF₃ F 4-fluorophenyl 177 OCH₂CH₃ H O CH₂CF₃ F 4-fluorophenyl 178 (CH₂)₂ O CH₂CF₃ F 4-fluorophenyl 179 (CH₂)₄ O CH₂CF₃ F 4-fluorophenyl 180 CH₃ H O CH₂CF₃ F 4-chlorophenyl 181 CH₂CH₃ H O CH₂CF₃ F 4-chlorophenyl 182 CH₂CF₃ H O CH₂CF₃ F 4-chlorophenyl 183 CH₂CH₂CH₃ H O CH₂CF₃ F 4-chlorophenyl 184 CH₂CH(CH₃)₂ H O CH₂CF₃ F 4-chlorophenyl 185 cyclopropylmethyl H O CH₂CF₃ F 4-chlorophenyl 186 SCH(CH₃)₂ H O CH₂CF₃ F 4-chlorophenyl 187 OCH₂CH₃ H O CH₂CF₃ F 4-chlorophenyl 188 (CH₂)₂ O CH₂CF₃ F 4-chlorophenyl 189 (CH₂)₄ O CH₂CF₃ F 4-chlorophenyl 190 CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 191 CH₂CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 192 CH₂CF₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 193 CH₂CH₂CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 194 CH₂CH(CH₃)₂ H O CH₂CF₃ F 4-trifluoromethylphenyl 195 cyclopropylmethyl H O CH₂CF₃ F 4-trifluoromethylphenyl 196 SCH(CH₃)₂ H O CH₂CF₃ F 4-trifluoromethylphenyl 197 OCH₂CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 198 (CH₂)₂ O CH₂CF₃ F 4-trifluoromethylphenyl 199 (CH₂)₄ O CH₂CF₃ F 4-trifluoromethylphenyl 200 CH₃ H O CH₂CF₃ F 4-methoxyphenyl 201 CH₂CH₃ H O CH₂CF₃ F 4-methoxyphenyl 202 CH₂CF₃ H O CH₂CF₃ F 4-methoxyphenyl 203 CH₂CH₂CH₃ H O CH₂CF₃ F 4-methoxyphenyl 204 CH₂CH(CH₃)₂ H O CH₂CF₃ F 4-methoxyphenyl 205 cyclopropylmethyl H O CH₂CF₃ F 4-methoxyphenyl 206 SCH(CH₃)₂ H O CH₂CF₃ F 4-methoxyphenyl 207 OCH₂CH₃ H O CH₂CF₃ F 4-methoxyphenyl 208 (CH₂)₂ O CH₂CF₃ F 4-methoxyphenyl 209 (CH₂)₄ O CH₂CF₃ F 4-methoxyphenyl 210 CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 211 CH₂CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 212 CH₂CF₃ H O CH₂CF₃ F 3,4 dichloro phenyl 213 CH₂CH₂CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 214 CH₂CH(CH₃)₂ H O CH₂CF₃ F 3,4 dichloro phenyl 215 cyclopropylmethyl H O CH₂CF₃ F 3,4 dichloro phenyl 216 SCH(CH₃)₂ H O CH₂CF₃ F 3,4 dichloro phenyl 217 OCH₂CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 218 (CH₂)₂ O CH₂CF₃ F 3,4 dichloro phenyl 219 (CH₂)₄ O CH₂CF₃ F 3,4 dichloro phenyl 220 CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 221 CH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 222 CH₂CF₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 223 CH₂CH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 224 CH₂CH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 225 cyclopropylmethyl H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 226 SCH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 227 OCH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 228 (CH₂)₂ O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 229 (CH₂)₄ O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 230 CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 231 CH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 232 CH₂CF₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 233 CH₂CH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 234 CH₂CH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 235 cyclopropylmethyl H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 236 SCH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 237 OCH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 238 (CH₂)₂ O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 239 (CH₂)₄ O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 240 CH₃ H O CH₂—c-Pr F 4-fluorophenyl 241 CH₂CH₃ H O CH₂—c-Pr F 4-fluorophenyl 242 CH₂CF₃ H O CH₂—c-Pr F 4-fluorophenyl 243 CH₂CH₂CH₃ H O CH₂—c-Pr F 4-fluorophenyl 244 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 4-fluorophenyl 245 cyclopropylmethyl H O CH₂—c-Pr F 4-fluorophenyl 246 SCH(CH₃)₂ H O CH₂—c-Pr F 4-fluorophenyl 247 OCH₂CH₃ H O CH₂—c-Pr F 4-fluorophenyl 248 (CH₂)₂ O CH₂—c-Pr F 4-fluorophenyl 249 (CH₂)₄ O CH₂—c-Pr F 4-fluorophenyl 250 CH₃ H O CH₂—c-Pr F 4-chlorophenyl 251 CH₂CH₃ H O CH₂—c-Pr F 4-chlorophenyl 252 CH₂CF₃ H O CH₂—c-Pr F 4-chlorophenyl 253 CH₂CH₂CH₃ H O CH₂—c-Pr F 4-chlorophenyl 254 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 4-chlorophenyl 255 cyclopropylmethyl H O CH₂—c-Pr F 4-chlorophenyl 256 SCH(CH₃)₂ H O CH₂—c-Pr F 4-chlorophenyl 257 OCH₂CH₃ H O CH₂—c-Pr F 4-chlorophenyl 258 (CH₂)₂ O CH₂—c-Pr F 4-chlorophenyl 259 (CH₂)₄ O CH₂—c-Pr F 4-chlorophenyl 260 CH₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 261 CH₂CH₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 262 CH₂CF₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 263 CH₂CH₂CH₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 264 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 4-trifluoromethylphenyl 265 cyclopropylmethyl H O CH₂—c-Pr F 4-trifluoromethylphenyl 266 SCH(CH₃)₂ H O CH₂—c-Pr F 4-trifluoromethylphenyl 267 OCH₂CH₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 268 (CH₂)₂ O CH₂—c-Pr F 4-trifluoromethylphenyl 269 (CH₂)₄ O CH₂—c-Pr F 4-trifluoromethylphenyl 270 CH₃ H O CH₂—c-Pr F 4-methoxyphenyl 271 CH₂CH₃ H O CH₂—c-Pr F 4-methoxyphenyl 272 CH₂CF₃ H O CH₂—c-Pr F 4-methoxyphenyl 273 CH₂CH₂CH₃ H O CH₂—c-Pr F 4-methoxyphenyl 274 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 4-methoxyphenyl 275 cyclopropylmethyl H O CH₂—c-Pr F 4-methoxyphenyl 276 SCH(CH₃)₂ H O CH₂—c-Pr F 4-methoxyphenyl 277 OCH₂CH₃ H O CH₂—c-Pr F 4-methoxyphenyl 278 (CH₂)₂ O CH₂—c-Pr F 4-methoxyphenyl 279 (CH₂)₄ O CH₂—c-Pr F 4-methoxyphenyl 280 CH₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 281 CH₂CH₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 282 CH₂CF₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 283 CH₂CH₂CH₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 284 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 3,4 dichloro phenyl 285 cyclopropylmethyl H O CH₂—c-Pr F 3,4 dichloro phenyl 286 SCH(CH₃)₂ H O CH₂—c-Pr F 3,4 dichloro phenyl 287 OCH₂CH₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 288 (CH₂)₂ O CH₂—c-Pr F 3,4 dichloro phenyl 289 (CH₂)₄ O CH₂—c-Pr F 3,4 dichloro phenyl 290 CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 291 CH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 292 CH₂CF₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 293 CH₂CH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 294 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 295 cyclopropylmethyl H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 296 SCH(CH₃)₂ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 297 OCH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 298 (CH₂)₂ O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 299 (CH₂)₄ O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 300 CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 301 CH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 302 CH₂CF₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 303 CH₂CH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 304 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 305 cyclopropylmethyl H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 306 SCH(CH₃)₂ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 307 OCH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 308 (CH₂)₂ O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 309 (CH₂)₄ O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 310 CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 311 CH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 312 CH₂CF₃ H O CH₂CH₃ Cl 4-fluorophenyl 313 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 314 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-fluorophenyl 315 cyclopropylmethyl H O CH₂CH₃ Cl 4-fluorophenyl 316 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-fluorophenyl 317 OCH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 318 (CH₂)₂ O CH₂CH₃ Cl 4-fluorophenyl 319 (CH₂)₄ O CH₂CH₃ Cl 4-fluorophenyl 320 CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 321 CH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 322 CH₂CF₃ H O CH₂CH₃ Cl 4-chlorophenyl 323 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 324 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-chlorophenyl 325 cyclopropylmethyl H O CH₂CH₃ Cl 4-chlorophenyl 326 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-chlorophenyl 327 OCH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 328 (CH₂)₂ O CH₂CH₃ Cl 4-chlorophenyl 329 (CH₂)₄ O CH₂CH₃ Cl 4-chlorophenyl 330 CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 331 CH₂CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 332 CH₂CF₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 333 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 334 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 335 cyclopropylmethyl H O CH₂CH₃ Cl 4-trifluoromethylphenyl 336 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 337 OCH₂CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 338 (CH₂)₂ O CH₂CH₃ Cl 4-trifluoromethylphenyl 339 (CH₂)₄ O CH₂CH₃ Cl 4-trifluoromethylphenyl 340 CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 341 CH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 342 CH₂CF₃ H O CH₂CH₃ Cl 4-methoxyphenyl 343 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 344 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-methoxyphenyl 345 cyclopropylmethyl H O CH₂CH₃ Cl 4-methoxyphenyl 346 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-methoxyphenyl 347 OCH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 348 (CH₂)₂ O CH₂CH₃ Cl 4-methoxyphenyl 349 (CH₂)₄ O CH₂CH₃ Cl 4-methoxyphenyl 350 CH₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 351 CH₂CH₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 352 CH₂CF₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 353 CH₂CH₂CH₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 354 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 3,4 dichloro phenyl 355 cyclopropylmethyl H O CH₂CH₃ Cl 3,4 dichloro phenyl 356 SCH(CH₃)₂ H O CH₂CH₃ Cl 3,4 dichloro phenyl 357 OCH₂CH₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 358 (CH₂)₂ O CH₂CH₃ Cl 3,4 dichloro phenyl 359 (CH₂)₄ O CH₂CH₃ Cl 3,4 dichloro phenyl 360 CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 361 CH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 362 CH₂CF₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 363 CH₂CH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 364 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 365 cyclopropylmethyl H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 366 SCH(CH₃)₂ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 367 OCH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 368 (CH₂)₂ O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 369 (CH₂)₄ O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 370 CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 371 CH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 372 CH₂CF₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 373 CH₂CH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 374 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 375 cyclopropylmethyl H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 376 SCH(CH₃)₂ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 377 OCH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 378 (CH₂)₂ O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 379 (CH₂)₄ O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 380 CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 381 CH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 382 CH₂CF₃ H O CH₂CF₃ Cl 4-fluorophenyl 383 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 384 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-fluorophenyl 385 cyclopropylmethyl H O CH₂CF₃ Cl 4-fluorophenyl 386 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-fluorophenyl 387 OCH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 388 (CH₂)₂ O O CH₂CF₃ Cl 4-fluorophenyl 389 (CH₂)₄ O O CH₂CF₃ Cl 4-fluorophenyl 400 CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 401 CH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 402 CH₂CF₃ H O CH₂CF₃ Cl 4-chlorophenyl 403 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 404 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-chlorophenyl 405 cyclopropylmethyl H O CH₂CF₃ Cl 4-chlorophenyl 406 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-chlorophenyl 407 OCH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 408 (CH₂)₂ O CH₂CF₃ Cl 4-chlorophenyl 409 (CH₂)₄ O CH₂CF₃ Cl 4-chlorophenyl 410 CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 411 CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 412 CH₂CF₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 413 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 414 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 415 cyclopropylmethyl H O CH₂CF₃ Cl 4-trifluoromethylphenyl 416 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 417 OCH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 418 (CH₂)₂ O CH₂CF₃ Cl 4-trifluoromethylphenyl 419 (CH₂)₄ O CH₂CF₃ Cl 4-trifluoromethylphenyl 420 CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 421 CH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 422 CH₂CF₃ H O CH₂CF₃ Cl 4-methoxyphenyl 423 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 424 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-methoxyphenyl 425 cyclopropylmethyl H O CH₂CF₃ Cl 4-methoxyphenyl 426 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-methoxyphenyl 427 OCH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 428 (CH₂)₂ O CH₂CF₃ Cl 4-methoxyphenyl 429 (CH₂)₄ O CH₂CF₃ Cl 4-methoxyphenyl 430 CH₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 431 CH₂CH₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 432 CH₂CF₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 433 CH₂CH₂CH₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 434 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 3,4 dichloro phenyl 435 cyclopropylmethyl H O CH₂CF₃ Cl 3,4 dichloro phenyl 436 SCH(CH₃)₂ H O CH₂CF₃ Cl 3,4 dichloro phenyl 437 OCH₂CH₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 438 (CH₂)₂ O CH₂CF₃ Cl 3,4 dichloro phenyl 439 (CH₂)₄ O CH₂CF₃ Cl 3,4 dichloro phenyl 440 CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 441 CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 442 CH₂CF₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 443 CH₂CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 444 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 445 cyclopropylmethyl H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 446 SCH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 447 OCH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 448 (CH₂)₂ O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 449 (CH₂)₄ O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 450 CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 451 CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 452 CH₂CF₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 453 CH₂CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 454 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 455 cyclopropylmethyl H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 456 SCH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 457 OCH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 458 (CH₂)₂ O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 459 (CH₂)₄ O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 460 CH₃ H O CH₂—c-Pr Cl 4-fluorophenyl 461 CH₂CH₃ H O CH₂—c-Pr Cl 4-fluorophenyl 462 CH₂CF₃ H O CH₂—c-Pr Cl 4-fluorophenyl 463 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-fluorophenyl 464 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-fluorophenyl 465 cyclopropylmethyl H O CH₂—c-Pr Cl 4-fluorophenyl 466 SCH(CH₃)₂ H O CH₂—c-Pr Cl 4-fluorophenyl 467 OCH₂CH₃ H O CH₂—c-Pr Cl 4-fluorophenyl 468 (CH₂)₂ O CH₂—c-Pr Cl 4-fluorophenyl 469 (CH₂)₄ O CH₂—c-Pr Cl 4-fluorophenyl 470 CH₃ H O CH₂—c-Pr Cl 4-chlorophenyl 471 CH₂CH₃ H O CH₂—c-Pr Cl 4-chlorophenyl 472 CH₂CF₃ H O CH₂—c-Pr Cl 4-chlorophenyl 473 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-chlorophenyl 474 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-chlorophenyl 475 cyclopropylmethyl H O CH₂—c-Pr Cl 4-chlorophenyl 476 SCH(CH₃)₂ H O CH₂—c-Pr Cl 4-chlorophenyl 477 OCH₂CH₃ H O CH₂—c-Pr Cl 4-chlorophenyl 478 (CH₂)₂ O CH₂—c-Pr Cl 4-chlorophenyl 479 (CH₂)₄ O CH₂—c-Pr Cl 4-chlorophenyl 480 CH₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 481 CH₂CH₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 482 CH₂CF₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 483 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 484 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 485 cyclopropylmethyl H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 486 SCH(CH₃)₂ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 487 OCH₂CH₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 488 (CH₂)₂ O CH₂—c-Pr Cl 4-trifluoromethylphenyl 489 (CH₂)₄ O CH₂—c-Pr Cl 4-trifluoromethylphenyl 490 CH₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 491 CH₂CH₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 492 CH₂CF₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 493 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 494 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-methoxyphenyl 495 cyclopropylmethyl H O CH₂—c-Pr Cl 4-methoxyphenyl 496 SCH(CH₃)₂ H O CH₂—c-Pr Cl 4-methoxyphenyl 497 OCH₂CH₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 498 (CH₂)₂ O CH₂—c-Pr Cl 4-methoxyphenyl 499 (CH₂)₄ O CH₂—c-Pr Cl 4-methoxyphenyl 500 CH₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 501 CH₂CH₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 502 CH₂CF₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 503 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 504 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 505 cyclopropylmethyl H O CH₂—c-Pr Cl 3,4 dichloro phenyl 506 SCH(CH₃)₂ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 507 OCH₂CH₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 508 (CH₂)₂ O CH₂—c-Pr Cl 3,4 dichloro phenyl 509 (CH₂)₄ O CH₂—c-Pr Cl 3,4 dichloro phenyl 510 CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 511 CH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 512 CH₂CF₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 513 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 514 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 515 cyclopropylmethyl H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 516 SCH(CH₃)₂ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 517 OCH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 518 (CH₂)₂ O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 519 (CH₂)₄ O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 520 CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 521 CH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 522 CH₂CF₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 523 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 524 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 525 cyclopropylmethyl H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 526 SCH(CH₃)₂ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 527 OCH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 528 (CH₂)₂ O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 529 (CH₂)₄ O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 530 CH₃ H O CH₂—c-Pr NO2 4-trifluoromethylphenyl 531 CH₂CH₃ H O CH₂—c-Pr NO2 4-trifluoromethylphenyl 532 CH₂CF₃ H O CH₂—c-Pr NO2 4-trifluoromethylphenyl 533 CH₂CH₂CH₃ H O CH₂—c-Pr NO2 4-trifluoromethylphenyl 534 CH₂CH(CH₃)₂ H O CH₂—c-Pr NO2 4-trifluoromethylphenyl 535 cyclopropylmethyl H O CH₂—c-Pr NO2 4-trifluoromethylphenyl 536 SCH(CH₃)₂ H O CH₂—c-Pr NO2 4-trifluoromethylphenyl 537 OCH₂CH₃ H O CH₂—c-Pr NO2 4-trifluoromethylphenyl 538 (CH₂)₂ O CH₂—c-Pr NO2 4-trifluoromethylphenyl 539 (CH₂)₄ O CH₂—c-Pr NO2 4-trifluoromethylphenyl 540 CH₃ H O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 541 CH₂CH₃ H O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 542 CH₂CF₃ H O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 543 CH₂CH₂CH₃ H O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 544 CH₂CH(CH₃)₂ H O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 545 cyclopropylmethyl H O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 546 SCH(CH₃)₂ H O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 547 OCH₂CH₃ H O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 548 (CH₂)₂ O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 549 (CH₂)₄ O CH₂—c-Pr NO2 5-benzo[c][1,2,5]oxadiazolyl 550 CH₃ H O CH₂—c-Pr NH2 4-trifluoromethylphenyl 551 CH₂CH₃ H O CH₂—c-Pr NH2 4-trifluoromethylphenyl 552 CH₂CF₃ H O CH₂—c-Pr NH2 4-trifluoromethylphenyl 553 CH₂CH₂CH₃ H O CH₂—c-Pr NH2 4-trifluoromethylphenyl 554 CH₂CH(CH₃)₂ H O CH₂—c-Pr NH2 4-trifluoromethylphenyl 555 cyclopropylmethyl H O CH₂—c-Pr NH2 4-trifluoromethylphenyl 556 SCH(CH₃)₂ H O CH₂—c-Pr NH2 4-trifluoromethylphenyl 557 OCH₂CH₃ H O CH₂—c-Pr NH2 4-trifluoromethylphenyl 558 (CH₂)₂ O CH₂—c-Pr NH2 4-trifluoromethylphenyl 559 (CH₂)₄ O CH₂—c-Pr NH2 4-trifluoromethylphenyl

TABLE 2 Formula V

EX R1 R2 X R3 R5 Z 560 CH₃ H O CH₂CH₃ F 4-fluorophenyl 561 CH₂CH₃ H O CH₂CH₃ F 4-fluorophenyl 562 CH₂CF₃ H O CH₂CH₃ F 4-fluorophenyl 563 CH₂CH₂CH₃ H O CH₂CH₃ F 4-fluorophenyl 564 CH₂CH(CH₃)₂ H O CH₂CH₃ F 4-fluorophenyl 565 cyclopropylmethyl H O CH₂CH₃ F 4-fluorophenyl 566 SCH(CH₃)₂ H O CH₂CH₃ F 4-fluorophenyl 567 OCH₂CH₃ H O CH₂CH₃ F 4-fluorophenyl 568 (CH₂)₂ O CH₂CH₃ F 4-fluorophenyl 569 (CH₂)₄ O CH₂CH₃ F 4-fluorophenyl 570 CH₃ H O CH₂CH₃ F 4-chlorophenyl 571 CH₂CH₃ H O CH₂CH₃ F 4-chlorophenyl 572 CH₂CF₃ H O CH₂CH₃ F 4-chlorophenyl 573 CH₂CH₂CH₃ H O CH₂CH₃ F 4-chlorophenyl 574 CH₂CH(CH₃)₂ H O CH₂CH₃ F 4-chlorophenyl 575 cyclopropylmethyl H O CH₂CH₃ F 4-chlorophenyl 576 SCH(CH₃)₂ H O CH₂CH₃ F 4-chlorophenyl 577 OCH₂CH₃ H O CH₂CH₃ F 4-chlorophenyl 578 (CH₂)₂ O CH₂CH₃ F 4-chlorophenyl 579 (CH₂)₄ O CH₂CH₃ F 4-chlorophenyl 580 CH₃ H O CH₂CH₃ F 4-trifluoromethylphenyl 581 CH₂CH₃ H O CH₂CH₃ F 4-trifluoromethylphenyl 582 CH₂CF₃ H O CH₂CH₃ F 4-trifluoromethylphenyl 583 CH₂CH₂CH₃ H O CH₂CH₃ F 4-trifluoromethylphenyl 584 CH₂CH(CH₃)₂ H O CH₂CH₃ F 4-trifluoromethylphenyl 585 cyclopropylmethyl H O CH₂CH₃ F 4-trifluoromethylphenyl 586 SCH(CH₃)₂ H O CH₂CH₃ F 4-trifluoromethylphenyl 587 OCH₂CH₃ H O CH₂CH₃ F 4-trifluoromethylphenyl 588 (CH₂)₂ O CH₂CH₃ F 4-trifluoromethylphenyl 589 (CH₂)₄ O CH₂CH₃ F 4-trifluoromethylphenyl 590 CH₃ H O CH₂CH₃ F 4-methoxyphenyl 591 CH₂CH₃ H O CH₂CH₃ F 4-methoxyphenyl 592 CH₂CF₃ H O CH₂CH₃ F 4-methoxyphenyl 593 CH₂CH₂CH₃ H O CH₂CH₃ F 4-methoxyphenyl 594 CH₂CH(CH₃)₂ H O CH₂CH₃ F 4-methoxyphenyl 595 cyclopropylmethyl H O CH₂CH₃ F 4-methoxyphenyl 596 SCH(CH₃)₂ H O CH₂CH₃ F 4-methoxyphenyl 597 OCH₂CH₃ H O CH₂CH₃ F 4-methoxyphenyl 598 (CH₂)₂ O CH₂CH₃ F 4-methoxyphenyl 599 (CH₂)₄ O CH₂CH₃ F 4-methoxyphenyl 600 CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 601 CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 602 CH₂CF₃ H O CH₂CH₃ F 3,4 dichloro phenyl 603 CH₂CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 604 CH₂CH(CH₃)₂ H O CH₂CH₃ F 3,4 dichloro phenyl 605 cyclopropylmethyl H O CH₂CH₃ F 3,4 dichloro phenyl 606 SCH(CH₃)₂ H O CH₂CH₃ F 3,4 dichloro phenyl 607 OCH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 608 (CH₂)₂ O CH₂CH₃ F 3,4 dichloro phenyl 609 (CH₂)₄ O CH₂CH₃ F 3,4 dichloro phenyl 610 CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 611 CH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 612 CH₂CF₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 613 CH₂CH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 614 CH₂CH(CH₃)₂ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 615 cyclopropylmethyl H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 616 SCH(CH₃)₂ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 617 OCH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 618 (CH₂)₂ O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 619 (CH₂)₄ O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 620 CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 621 CH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 622 CH₂CF₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 623 CH₂CH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 624 CH₂CH(CH₃)₂ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 625 cyclopropylmethyl H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 626 SCH(CH₃)₂ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 627 OCH₂CH₃ H O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 628 (CH₂)₂ O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 629 (CH₂)₄ O CH₂CH₃ F 5-benzo[c][1,2,5]thiadiazolyl 630 CH₃ H O CH₂CF₃ F 4-fluorophenyl 631 CH₂CH₃ H O CH₂CF₃ F 4-fluorophenyl 632 CH₂CF₃ H O CH₂CF₃ F 4-fluorophenyl 633 CH₂CH₂CH₃ H O CH₂CF₃ F 4-fluorophenyl 634 CH₂CH(CH₃)₂ H O CH₂CF₃ F 4-fluorophenyl 635 cyclopropylmethyl H O CH₂CF₃ F 4-fluorophenyl 636 SCH(CH₃)₂ H O CH₂CF₃ F 4-fluorophenyl 637 OCH₂CH₃ H O CH₂CF₃ F 4-fluorophenyl 638 (CH₂)₂ O CH₂CF₃ F 4-fluorophenyl 639 (CH₂)₄ O CH₂CF₃ F 4-fluorophenyl 640 CH₃ H O CH₂CF₃ F 4-chlorophenyl 641 CH₂CH₃ H O CH₂CF₃ F 4-chlorophenyl 642 CH₂CF₃ H O CH₂CF₃ F 4-chlorophenyl 643 CH₂CH₂CH₃ H O CH₂CF₃ F 4-chlorophenyl 644 CH₂CH(CH₃)₂ H O CH₂CF₃ F 4-chlorophenyl 645 cyclopropylmethyl H O CH₂CF₃ F 4-chlorophenyl 646 SCH(CH₃)₂ H O CH₂CF₃ F 4-chlorophenyl 647 OCH₂CH₃ H O CH₂CF₃ F 4-chlorophenyl 648 (CH₂)₂ O CH₂CF₃ F 4-chlorophenyl 649 (CH₂)₄ O CH₂CF₃ F 4-chlorophenyl 650 CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 651 CH₂CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 652 CH₂CF₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 653 CH₂CH₂CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 654 CH₂CH(CH₃)₂ H O CH₂CF₃ F 4-trifluoromethylphenyl 655 cyclopropylmethyl H O CH₂CF₃ F 4-trifluoromethylphenyl 656 SCH(CH₃)₂ H O CH₂CF₃ F 4-trifluoromethylphenyl 657 OCH₂CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 658 (CH₂)₂ O CH₂CF₃ F 4-trifluoromethylphenyl 659 (CH₂)₄ O CH₂CF₃ F 4-trifluoromethylphenyl 660 CH₃ H O CH₂CF₃ F 4-methoxyphenyl 661 CH₂CH₃ H O CH₂CF₃ F 4-methoxyphenyl 662 CH₂CF₃ H O CH₂CF₃ F 4-methoxyphenyl 663 CH₂CH₂CH₃ H O CH₂CF₃ F 4-methoxyphenyl 664 CH₂CH(CH₃)₂ H O CH₂CF₃ F 4-methoxyphenyl 665 cyclopropylmethyl H O CH₂CF₃ F 4-methoxyphenyl 666 SCH(CH₃)₂ H O CH₂CF₃ F 4-methoxyphenyl 667 OCH₂CH₃ H O CH₂CF₃ F 4-methoxyphenyl 668 (CH₂)₂ O CH₂CF₃ F 4-methoxyphenyl 669 (CH₂)₄ O CH₂CF₃ F 4-methoxyphenyl 670 CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 671 CH₂CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 672 CH₂CF₃ H O CH₂CF₃ F 3,4 dichloro phenyl 673 CH₂CH₂CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 674 CH₂CH(CH₃)₂ H O CH₂CF₃ F 3,4 dichloro phenyl 675 cyclopropylmethyl H O CH₂CF₃ F 3,4 dichloro phenyl 676 SCH(CH₃)₂ H O CH₂CF₃ F 3,4 dichloro phenyl 677 OCH₂CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 678 (CH₂)₂ O CH₂CF₃ F 3,4 dichloro phenyl 679 (CH₂)₄ O CH₂CF₃ F 3,4 dichloro phenyl 680 CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 681 CH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 682 CH₂CF₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 683 CH₂CH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 684 CH₂CH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 685 cyclopropylmethyl H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 686 SCH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 687 OCH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 688 (CH₂)₂ O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 689 (CH₂)₄ O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 690 CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 691 CH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 692 CH₂CF₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 693 CH₂CH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 694 CH₂CH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 695 cyclopropylmethyl H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 696 SCH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 697 OCH₂CH₃ H O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 698 (CH₂)₂ O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 699 (CH₂)₄ O CH₂CF₃ F 5-benzo[c][1,2,5]thiadiazolyl 700 CH₃ H O CH₂—c-Pr F 4-fluorophenyl 701 CH₂CH₃ H O CH₂—c-Pr F 4-fluorophenyl 702 CH₂CF₃ H O CH₂—c-Pr F 4-fluorophenyl 703 CH₂CH₂CH₃ H O CH₂—c-Pr F 4-fluorophenyl 704 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 4-fluorophenyl 705 cyclopropylmethyl H O CH₂—c-Pr F 4-fluorophenyl 706 SCH(CH₃)₂ H O CH₂—c-Pr F 4-fluorophenyl 707 OCH₂CH₃ H O CH₂—c-Pr F 4-fluorophenyl 708 (CH₂)₂ O CH₂—c-Pr F 4-fluorophenyl 709 (CH₂)₄ O CH₂—c-Pr F 4-fluorophenyl 710 CH₃ H O CH₂—c-Pr F 4-chlorophenyl 711 CH₂CH₃ H O CH₂—c-Pr F 4-chlorophenyl 712 CH₂CF₃ H O CH₂—c-Pr F 4-chlorophenyl 713 CH₂CH₂CH₃ H O CH₂—c-Pr F 4-chlorophenyl 714 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 4-chlorophenyl 715 cyclopropylmethyl H O CH₂—c-Pr F 4-chlorophenyl 716 SCH(CH₃)₂ H O CH₂—c-Pr F 4-chlorophenyl 717 OCH₂CH₃ H O CH₂—c-Pr F 4-chlorophenyl 718 (CH₂)₂ O CH₂—c-Pr F 4-chlorophenyl 719 (CH₂)₄ O CH₂—c-Pr F 4-chlorophenyl 720 CH₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 721 CH₂CH₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 722 CH₂CF₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 723 CH₂CH₂CH₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 724 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 4-trifluoromethylphenyl 725 cyclopropylmethyl H O CH₂—c-Pr F 4-trifluoromethylphenyl 726 SCH(CH₃)₂ H O CH₂—c-Pr F 4-trifluoromethylphenyl 727 OCH₂CH₃ H O CH₂—c-Pr F 4-trifluoromethylphenyl 728 (CH₂)₂ O CH₂—c-Pr F 4-trifluoromethylphenyl 729 (CH₂)₄ O CH₂—c-Pr F 4-trifluoromethylphenyl 730 CH₃ H O CH₂—c-Pr F 4-methoxyphenyl 731 CH₂CH₃ H O CH₂—c-Pr F 4-methoxyphenyl 732 CH₂CF₃ H O CH₂—c-Pr F 4-methoxyphenyl 733 CH₂CH₂CH₃ H O CH₂—c-Pr F 4-methoxyphenyl 734 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 4-methoxyphenyl 735 cyclopropylmethyl H O CH₂—c-Pr F 4-methoxyphenyl 736 SCH(CH₃)₂ H O CH₂—c-Pr F 4-methoxyphenyl 737 OCH₂CH₃ H O CH₂—c-Pr F 4-methoxyphenyl 738 (CH₂)₂ O CH₂—c-Pr F 4-methoxyphenyl 739 (CH₂)₄ O CH₂—c-Pr F 4-methoxyphenyl 740 CH₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 741 CH₂CH₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 742 CH₂CF₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 743 CH₂CH₂CH₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 744 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 3,4 dichloro phenyl 745 cyclopropylmethyl H O CH₂—c-Pr F 3,4 dichloro phenyl 746 SCH(CH₃)₂ H O CH₂—c-Pr F 3,4 dichloro phenyl 747 OCH₂CH₃ H O CH₂—c-Pr F 3,4 dichloro phenyl 748 (CH₂)₂ O CH₂—c-Pr F 3,4 dichloro phenyl 749 (CH₂)₄ O CH₂—c-Pr F 3,4 dichloro phenyl 750 CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 751 CH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 752 CH₂CF₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 753 CH₂CH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 754 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 755 cyclopropylmethyl H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 756 SCH(CH₃)₂ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 757 OCH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 758 (CH₂)₂ O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 759 (CH₂)₄ O CH₂—c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 760 CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 761 CH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 762 CH₂CF₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 763 CH₂CH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 764 CH₂CH(CH₃)₂ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 765 cyclopropylmethyl H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 766 SCH(CH₃)₂ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 767 OCH₂CH₃ H O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 768 (CH₂)₂ O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 769 (CH₂)₄ O CH₂—c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 770 CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 771 CH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 772 CH₂CF₃ H O CH₂CH₃ Cl 4-fluorophenyl 773 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 774 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-fluorophenyl 775 cyclopropylmethyl H O CH₂CH₃ Cl 4-fluorophenyl 776 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-fluorophenyl 777 OCH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 778 (CH₂)₂ O CH₂CH₃ Cl 4-fluorophenyl 779 (CH₂)₄ O CH₂CH₃ Cl 4-fluorophenyl 780 CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 781 CH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 782 CH₂CF₃ H O CH₂CH₃ Cl 4-chlorophenyl 783 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 784 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-chlorophenyl 785 cyclopropylmethyl H O CH₂CH₃ Cl 4-chlorophenyl 786 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-chlorophenyl 787 OCH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 788 (CH₂)₂ O CH₂CH₃ Cl 4-chlorophenyl 789 (CH₂)₄ O CH₂CH₃ Cl 4-chlorophenyl 790 CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 791 CH₂CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 792 CH₂CF₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 793 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 794 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 795 cyclopropylmethyl H O CH₂CH₃ Cl 4-trifluoromethylphenyl 796 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 797 OCH₂CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 798 (CH₂)₂ O CH₂CH₃ Cl 4-trifluoromethylphenyl 799 (CH₂)₄ O CH₂CH₃ Cl 4-trifluoromethylphenyl 800 CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 801 CH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 802 CH₂CF₃ H O CH₂CH₃ Cl 4-methoxyphenyl 803 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 804 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-methoxyphenyl 805 cyclopropylmethyl H O CH₂CH₃ Cl 4-methoxyphenyl 806 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-methoxyphenyl 807 OCH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 808 (CH₂)₂ O CH₂CH₃ Cl 4-methoxyphenyl 809 (CH₂)₄ O CH₂CH₃ Cl 4-methoxyphenyl 810 CH₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 811 CH₂CH₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 812 CH₂CF₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 813 CH₂CH₂CH₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 814 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 3,4 dichloro phenyl 815 cyclopropylmethyl H O CH₂CH₃ Cl 3,4 dichloro phenyl 816 SCH(CH₃)₂ H O CH₂CH₃ Cl 3,4 dichloro phenyl 817 OCH₂CH₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 818 (CH₂)₂ O CH₂CH₃ Cl 3,4 dichloro phenyl 819 (CH₂)₄ O CH₂CH₃ Cl 3,4 dichloro phenyl 820 CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 821 CH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 822 CH₂CF₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 823 CH₂CH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 824 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 825 cyclopropylmethyl H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 826 SCH(CH₃)₂ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 827 OCH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 828 (CH₂)₂ O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 829 (CH₂)₄ O CH₂CH₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 830 CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 831 CH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 832 CH₂CF₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 833 CH₂CH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 834 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 835 cyclopropylmethyl H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 836 SCH(CH₃)₂ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 837 OCH₂CH₃ H O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 838 (CH₂)₂ O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 839 (CH₂)₄ O CH₂CH₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 840 CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 841 CH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 842 CH₂CF₃ H O CH₂CF₃ Cl 4-fluorophenyl 843 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 844 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-fluorophenyl 845 cyclopropylmethyl H O CH₂CF₃ Cl 4-fluorophenyl 846 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-fluorophenyl 847 OCH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 848 (CH₂)₂ O O CH₂CF₃ Cl 4-fluorophenyl 849 (CH₂)₄ O O CH₂CF₃ Cl 4-fluorophenyl 850 CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 851 CH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 852 CH₂CF₃ H O CH₂CF₃ Cl 4-chlorophenyl 853 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 854 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-chlorophenyl 855 cyclopropylmethyl H O CH₂CF₃ Cl 4-chlorophenyl 856 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-chlorophenyl 857 OCH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 858 (CH₂)₂ O CH₂CF₃ Cl 4-chlorophenyl 859 (CH₂)₄ O CH₂CF₃ Cl 4-chlorophenyl 860 CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 861 CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 862 CH₂CF₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 863 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 864 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 865 cyclopropylmethyl H O CH₂CF₃ Cl 4-trifluoromethylphenyl 866 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 867 OCH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 868 (CH₂)₂ O CH₂CF₃ Cl 4-trifluoromethylphenyl 869 (CH₂)₄ O CH₂CF₃ Cl 4-trifluoromethylphenyl 870 CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 871 CH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 872 CH₂CF₃ H O CH₂CF₃ Cl 4-methoxyphenyl 873 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 874 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-methoxyphenyl 875 cyclopropylmethyl H O CH₂CF₃ Cl 4-methoxyphenyl 876 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-methoxyphenyl 877 OCH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 878 (CH₂)₂ O CH₂CF₃ Cl 4-methoxyphenyl 879 (CH₂)₄ O CH₂CF₃ Cl 4-methoxyphenyl 880 CH₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 881 CH₂CH₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 882 CH₂CF₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 883 CH₂CH₂CH₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 884 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 3,4 dichloro phenyl 885 cyclopropylmethyl H O CH₂CF₃ Cl 3,4 dichloro phenyl 886 SCH(CH₃)₂ H O CH₂CF₃ Cl 3,4 dichloro phenyl 887 OCH₂CH₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 888 (CH₂)₂ O CH₂CF₃ Cl 3,4 dichloro phenyl 889 (CH₂)₄ O CH₂CF₃ Cl 3,4 dichloro phenyl 890 CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 891 CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 892 CH₂CF₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 893 CH₂CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 894 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 895 cyclopropylmethyl H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 896 SCH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 897 OCH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 898 (CH₂)₂ O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 899 (CH₂)₄ O CH₂CF₃ Cl 5-benzo[c][1,2,5]oxadiazolyl 900 CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 901 CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 902 CH₂CF₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 903 CH₂CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 904 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 905 cyclopropylmethyl H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 906 SCH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 907 OCH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 908 (CH₂)₂ O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 909 (CH₂)₄ O CH₂CF₃ Cl 5-benzo[c][1,2,5]thiadiazolyl 910 CH₃ H O CH₂—c-Pr Cl 4-fluorophenyl 911 CH₂CH₃ H O CH₂—c-Pr Cl 4-fluorophenyl 912 CH₂CF₃ H O CH₂—c-Pr Cl 4-fluorophenyl 913 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-fluorophenyl 914 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-fluorophenyl 915 cyclopropylmethyl H O CH₂—c-Pr Cl 4-fluorophenyl 916 SCH(CH₃)₂ H O CH₂—c-Pr Cl 4-fluorophenyl 917 OCH₂CH₃ H O CH₂—c-Pr Cl 4-fluorophenyl 918 (CH₂)₂ O CH₂—c-Pr Cl 4-fluorophenyl 919 (CH₂)₄ O CH₂—c-Pr Cl 4-fluorophenyl 920 CH₃ H O CH₂—c-Pr Cl 4-chlorophenyl 921 CH₂CH₃ H O CH₂—c-Pr Cl 4-chlorophenyl 922 CH₂CF₃ H O CH₂—c-Pr Cl 4-chlorophenyl 923 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-chlorophenyl 924 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-chlorophenyl 925 cyclopropylmethyl H O CH₂—c-Pr Cl 4-chlorophenyl 926 SCH(CH₃)₂ H O CH₂—c-Pr Cl 4-chlorophenyl 927 OCH₂CH₃ H O CH₂—c-Pr Cl 4-chlorophenyl 928 (CH₂)₂ O CH₂—c-Pr Cl 4-chlorophenyl 929 (CH₂)₄ O CH₂—c-Pr Cl 4-chlorophenyl 930 CH₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 931 CH₂CH₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 932 CH₂CF₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 933 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 934 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 935 cyclopropylmethyl H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 936 SCH(CH₃)₂ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 937 OCH₂CH₃ H O CH₂—c-Pr Cl 4-trifluoromethylphenyl 938 (CH₂)₂ O CH₂—c-Pr Cl 4-trifluoromethylphenyl 939 (CH₂)₄ O CH₂—c-Pr Cl 4-trifluoromethylphenyl 940 CH₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 941 CH₂CH₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 942 CH₂CF₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 943 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 944 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-methoxyphenyl 945 cyclopropylmethyl H O CH₂—c-Pr Cl 4-methoxyphenyl 946 SCH(CH₃)₂ H O CH₂—c-Pr Cl 4-methoxyphenyl 947 OCH₂CH₃ H O CH₂—c-Pr Cl 4-methoxyphenyl 948 (CH₂)₂ O CH₂—c-Pr Cl 4-methoxyphenyl 949 (CH₂)₄ O CH₂—c-Pr Cl 4-methoxyphenyl 950 CH₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 951 CH₂CH₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 952 CH₂CF₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 953 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 954 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 955 cyclopropylmethyl H O CH₂—c-Pr Cl 3,4 dichloro phenyl 956 SCH(CH₃)₂ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 957 OCH₂CH₃ H O CH₂—c-Pr Cl 3,4 dichloro phenyl 958 (CH₂)₂ O CH₂—c-Pr Cl 3,4 dichloro phenyl 959 (CH₂)₄ O CH₂—c-Pr Cl 3,4 dichloro phenyl 960 CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 961 CH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 962 CH₂CF₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 963 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 964 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 965 cyclopropylmethyl H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 966 SCH(CH₃)₂ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 967 OCH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 968 (CH₂)₂ O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 969 (CH₂)₄ O CH₂—c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 970 CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 971 CH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 972 CH₂CF₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 973 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 974 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 975 cyclopropylmethyl H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 976 SCH(CH₃)₂ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 977 OCH₂CH₃ H O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 978 (CH₂)₂ O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 979 (CH₂)₄ O CH₂—c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl

TABLE 3 Formula III

Compounds of Formula III Ex R1 R2 Y R4 R5 Z  980 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  981 CH₂CF₃ H O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  982 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  983 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  984 cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  985 cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  986 (CH₂)₂ O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  987 (CH₂)₃ O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  988 (CH₂)₄ O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  989 (CH₂)₅ O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  990 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  991 Cyclopentyl H O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl  992 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-tolyl  993 CH₂CF₃ H O CH₂ CF₃ CF₃ 4-tolyl  994 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-tolyl  995 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-tolyl  996 cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-tolyl  997 cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-tolyl  998 (CH₂)₂ O CH₂ CF₃ CF₃ 4-tolyl  999 (CH₂)₃ O CH₂ CF₃ CF₃ 4-tolyl 1000 (CH₂)₄ O CH₂ CF₃ CF₃ 4-tolyl 1001 (CH₂)₅ O CH₂ CF₃ CF₃ 4-tolyl 1002 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-tolyl 1003 Cyclopentyl H O CH₂ CF₃ CF₃ 4-tolyl 1004 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1005 CH₂CF₃ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1006 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1007 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1008 cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1009 cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1010 (CH₂)₂ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1011 (CH₂)₃ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1012 (CH₂)₄ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1013 (CH₂)₅ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1014 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-ethyl phenyl 1015 Cyclopentyl H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1016 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1017 CH₂CF₃ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1018 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1019 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1020 cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1021 cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1022 (CH₂)₂ O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1023 (CH₂)₃ O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1024 (CH₂)₄ O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1025 (CH₂)₅ O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1026 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1027 Cyclopentyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1028 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1029 CH₂CF₃ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1030 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1031 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1032 cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1033 cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1034 (CH₂)₂ O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1035 (CH₂)₃ O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1036 (CH₂)₄ O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1037 (CH₂)₅ O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1038 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1039 Cyclopentyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1040 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1041 CH₂CF₃ H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1042 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1043 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1044 cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1045 cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1046 (CH₂)₂ O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1047 (CH₂)₃ O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1048 (CH₂)₄ O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1049 (CH₂)₅ O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1050 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1051 Cyclopentyl H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1052 CH₂CH₃ H O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1053 CH₂CF₃ H O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1054 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1055 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1056 cyclopropylmethyl H O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1057 cyclobutylmethyl H O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1058 (CH₂)₂ O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1059 (CH₂)₃ O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1060 (CH₂)₄ O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1061 (CH₂)₅ O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1062 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1063 Cyclopentyl H O CH₂—c-Pr CF₃ 4-trifluoromethylphenyl 1064 CH₂CH₃ H O CH₂—c-Pr CF₃ 4-tolyl 1065 CH₂CF₃ H O CH₂—c-Pr CF₃ 4-tolyl 1066 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃ 4-tolyl 1067 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃ 4-tolyl 1068 cyclopropylmethyl H O CH₂—c-Pr CF₃ 4-tolyl 1069 cyclobutylmethyl H O CH₂—c-Pr CF₃ 4-tolyl 1070 (CH₂)₂ O CH₂—c-Pr CF₃ 4-tolyl 1071 (CH₂)₃ O CH₂—c-Pr CF₃ 4-tolyl 1072 (CH₂)₄ O CH₂—c-Pr CF₃ 4-tolyl 1073 (CH₂)₅ O CH₂—c-Pr CF₃ 4-tolyl 1074 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃ 4-tolyl 1075 Cyclopentyl H O CH₂—c-Pr CF₃ 4-tolyl 1076 CH₂CH₃ H O CH₂—c-Pr CF₃ 4-ethyl phenyl 1077 CH₂CF₃ H O CH₂—c-Pr CF₃ 4-ethyl phenyl 1078 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃ 4-ethyl phenyl 1079 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃ 4-ethyl phenyl 1080 cyclopropylmethyl H O CH₂—c-Pr CF₃ 4-ethyl phenyl 1081 cyclobutylmethyl H O CH₂—c-Pr CF₃ 4-ethyl phenyl 1082 (CH₂)₂ O CH₂—c-Pr CF₃ 4-ethyl phenyl 1083 (CH₂)₃ O CH₂—c-Pr CF₃ 4-ethyl phenyl 1084 (CH₂)₄ O CH₂—c-Pr CF₃ 4-ethyl phenyl 1085 (CH₂)₅ O CH₂—c-Pr CF₃ 4-ethyl phenyl 1086 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃ 4-ethyl phenyl 1087 Cyclopentyl H O CH₂—c-Pr CF₃ 4-ethyl phenyl 1088 CH₂CH₃ H O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1089 CH₂CF₃ H O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1090 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1091 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1092 cyclopropylmethyl H O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1093 cyclobutylmethyl H O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1094 (CH₂)₂ O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1095 (CH₂)₃ O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1096 (CH₂)₄ O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1097 (CH₂)₅ O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1098 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1099 Cyclopentyl H O CH₂—c-Pr CF₃ 4-isopropyl phenyl 1100 CH₂CH₃ H O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1101 CH₂CF₃ H O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1102 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1103 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1104 cyclopropylmethyl H O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1105 cyclobutylmethyl H O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1106 (CH₂)₂ O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1107 (CH₂)₃ O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1108 (CH₂)₄ O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1109 (CH₂)₅ O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1110 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1111 Cyclopentyl H O CH₂—c-Pr CF₃ 4-thiomethylphenyl 1112 CH₂CH₃ H O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1113 CH₂CF₃ H O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1114 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1115 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1116 cyclopropylmethyl H O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1117 cyclobutylmethyl H O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1118 (CH₂)₂ O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1119 (CH₂)₃ O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1120 (CH₂)₄ O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1121 (CH₂)₅ O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1122 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1123 Cyclopentyl H O CH₂—c-Pr CF₃ 4-trifluoromethoxyphenyl 1124 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1125 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1126 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1127 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1128 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1129 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1130 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1131 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1132 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1133 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1134 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1135 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethylphenyl 1136 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1137 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1138 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1139 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1140 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1141 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1142 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1143 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1144 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1145 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1146 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1147 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1148 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1149 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1150 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1151 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1152 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1153 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1154 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1155 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1156 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1157 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1158 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1159 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1160 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1161 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1162 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1163 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1164 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1165 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1166 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1167 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1168 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1169 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1170 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1171 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1172 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1173 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1174 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1175 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1176 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1177 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1178 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1179 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1180 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1181 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1182 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1183 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1184 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1185 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1186 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1187 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1188 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1189 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1190 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1191 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1192 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1193 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1194 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1195 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-trifluoromethoxyphenyl 1196 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1197 CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1198 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1199 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1200 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1201 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1202 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1203 (CH₂)₃ O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1204 (CH₂)₄ O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1205 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1206 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1207 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethylphenyl 1208 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1209 CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1210 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1211 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1212 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1213 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1214 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1215 (CH₂)₃ O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1216 (CH₂)₄ O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1217 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1218 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1219 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1220 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1221 CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1222 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1223 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1224 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1225 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1226 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1227 (CH₂)₃ O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1228 (CH₂)₄ O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1229 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1230 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1231 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1232 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1233 CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1234 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1235 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1236 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1237 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1238 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1239 (CH₂)₃ O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1240 (CH₂)₄ O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1241 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1242 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1243 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1244 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1245 CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1246 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1247 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1248 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1249 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1250 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1251 (CH₂)₃ O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1252 (CH₂)₄ O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1253 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1254 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1255 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1256 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1257 CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1258 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1259 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1260 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1261 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1262 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1263 (CH₂)₃ O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1264 (CH₂)₄ O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1265 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1266 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1267 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl

TABLE 4 Compounds of Formula III Formula III

Ex R1 R2 Y R4 R5 Z 1268 cyclobutyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methylphenyl 1269 (CH₂)₃ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1270 (CH₂)₅ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1271 5,5-spiro[2.3] O CH₂CF₃ Cl 4-trifluoro- hexane methylphenyl 1272 Cyclopentyl H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1273 CH₂CH₃ H O CH₂CF₃ Cl 4-tolyl 1274 CH₂CF₃ H O CH₂CF₃ Cl 4-tolyl 1275 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-tolyl 1276 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-tolyl 1277 cyclopropyl- H O CH₂CF₃ Cl 4-tolyl methyl 1278 cyclobutyl- H O CH₂CF₃ Cl 4-tolyl methyl 1279 (CH₂)₂ O CH₂CF₃ Cl 4-tolyl 1280 (CH₂)₃ O CH₂CF₃ Cl 4-tolyl 1281 (CH₂)₄ O CH₂CF₃ Cl 4-tolyl 1282 (CH₂)₅ O CH₂CF₃ Cl 4-tolyl 1283 5,5-spiro[2.3] O CH₂CF₃ Cl 4-tolyl hexane 1284 Cyclopentyl H O CH₂CF₃ Cl 4-tolyl 1285 CH₂CH₃ H O CH₂CF₃ Cl 4-ethylphenyl 1286 CH₂CF₃ H O CH₂CF₃ Cl 4-ethylphenyl 1287 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-ethylphenyl 1288 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-ethylphenyl 1289 cyclopropyl- H O CH₂CF₃ Cl 4-ethylphenyl methyl 1290 cyclobutyl- H O CH₂CF₃ Cl 4-ethylphenyl methyl 1291 (CH₂)₂ O CH₂CF₃ Cl 4-ethylphenyl 1292 (CH₂)₃ O CH₂CF₃ Cl 4-ethylphenyl 1293 (CH₂)₄ O CH₂CF₃ Cl 4-ethylphenyl 1294 (CH₂)₅ O CH₂CF₃ Cl 4-ethylphenyl 1295 5,5-spiro[2.3] O CH₂CF₃ Cl 4-ethylphenyl hexane 1296 Cyclopentyl H O CH₂CF₃ Cl 4-ethylphenyl 1297 CH₂CH₃ H O CH₂CF₃ Cl 4-isopropyl- phenyl 1298 CH₂CF₃ H O CH₂CF₃ Cl 4-isopropyl- phenyl 1299 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-isopropyl- phenyl 1300 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-isopropyl- phenyl 1301 cyclopropyl- H O CH₂CF₃ Cl 4-isopropyl- methyl phenyl 1302 cyclobutyl- H O CH₂CF₃ Cl 4-isopropyl- methyl phenyl 1303 (CH₂)₂ O CH₂CF₃ Cl 4-isopropyl- phenyl 1304 (CH₂)₃ O CH₂CF₃ Cl 4-isopropyl- phenyl 1305 (CH₂)₄ O CH₂CF₃ Cl 4-isopropyl- phenyl 1306 (CH₂)₅ O CH₂CF₃ Cl 4-isopropyl- phenyl 1307 5,5-spiro[2.3] O CH₂CF₃ Cl 4-isopropyl- hexane phenyl 1308 Cyclopentyl H O CH₂CF₃ Cl 4-isopropyl- phenyl 1309 CH₂CH₃ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1310 CH₂CF₃ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1311 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1312 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1313 cyclopropyl- H O CH₂CF₃ Cl 4-thiomethyl- methyl phenyl 1314 cyclobutyl- H O CH₂CF₃ Cl 4-thiomethyl- methyl phenyl 1315 (CH₂)₂ O CH₂CF₃ Cl 4-thiomethyl- phenyl 1316 (CH₂)₃ O CH₂CF₃ Cl 4-thiomethyl- phenyl 1317 (CH₂)₄ O CH₂CF₃ Cl 4-thiomethyl- phenyl 1318 (CH₂)₅ O CH₂CF₃ Cl 4-thiomethyl- phenyl 1319 5,5-spiro[2.3] O CH₂CF₃ Cl 4-thiomethyl- hexane phenyl 1320 Cyclopentyl H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1321 CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1322 CH₂CF₃ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1323 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1324 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1325 cyclopropyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methoxyphenyl 1326 cyclobutyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methoxyphenyl 1327 (CH₂)₂ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1328 (CH₂)₃ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1329 (CH₂)₄ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1330 (CH₂)₅ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1331 5,5-spiro[2.3] O CH₂CF₃ Cl 4-trifluoro- hexane methoxyphenyl 1332 Cyclopentyl H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1333 cyclobutyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methylphenyl 1334 (CH₂)₃ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1335 (CH₂)₅ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1336 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-trifluoro- hexane methylphenyl 1337 Cyclopentyl H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1338 CH₂CH₃ H O CH₂-c-Pr Cl 4-tolyl 1339 CH₂CF₃ H O CH₂-c-Pr Cl 4-tolyl 1340 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-tolyl 1341 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-tolyl 1342 cyclopropyl- H O CH₂-c-Pr Cl 4-tolyl methyl 1343 cyclobutyl- H O CH₂-c-Pr Cl 4-tolyl methyl 1344 (CH₂)₂ O CH₂-c-Pr Cl 4-tolyl 1345 (CH₂)₃ O CH₂-c-Pr Cl 4-tolyl 1346 (CH₂)₄ O CH₂-c-Pr Cl 4-tolyl 1347 (CH₂)₅ O CH₂-c-Pr Cl 4-tolyl 1348 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-tolyl hexane 1349 Cyclopentyl H O CH₂-c-Pr Cl 4-tolyl 1350 CH₂CH₃ H O CH₂-c-Pr Cl 4-ethylphenyl 1351 CH₂CF₃ H O CH₂-c-Pr Cl 4-ethylphenyl 1352 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-ethylphenyl 1353 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-ethylphenyl 1354 cyclopropyl- H O CH₂-c-Pr Cl 4-ethylphenyl methyl 1355 cyclobutyl- H O CH₂-c-Pr Cl 4-ethylphenyl methyl 1356 (CH₂)₂ O CH₂-c-Pr Cl 4-ethylphenyl 1357 (CH₂)₃ O CH₂-c-Pr Cl 4-ethylphenyl 1358 (CH₂)₄ O CH₂-c-Pr Cl 4-ethylphenyl 1359 (CH₂)₅ O CH₂-c-Pr Cl 4-ethylphenyl 1360 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-ethylphenyl hexane 1361 Cyclopentyl H O CH₂-c-Pr Cl 4-ethylphenyl 1362 CH₂CH₃ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1363 CH₂CF₃ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1364 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1365 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1366 cyclopropyl- H O CH₂-c-Pr Cl 4-isopropyl- methyl phenyl 1367 cyclobutyl- H O CH₂-c-Pr Cl 4-isopropyl- methyl phenyl 1368 (CH₂)₂ O CH₂-c-Pr Cl 4-isopropyl- phenyl 1369 (CH₂)₃ O CH₂-c-Pr Cl 4-isopropyl- phenyl 1370 (CH₂)₄ O CH₂-c-Pr Cl 4-isopropyl- phenyl 1371 (CH₂)₅ O CH₂-c-Pr Cl 4-isopropyl- phenyl 1372 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-isopropyl- hexane phenyl 1373 Cyclopentyl H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1374 CH₂CH₃ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1375 CH₂CF₃ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1376 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1377 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1378 cyclopropyl- H O CH₂-c-Pr Cl 4-thiomethyl- methyl phenyl 1379 cyclobutyl- H O CH₂-c-Pr Cl 4-thiomethyl- methyl phenyl 1380 (CH₂)₂ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1381 (CH₂)₃ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1382 (CH₂)₄ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1383 (CH₂)₅ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1384 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-thiomethyl- hexane phenyl 1385 Cyclopentyl H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1386 CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1387 CH₂CF₃ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1388 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1389 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1390 cyclopropyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1391 cyclobutyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1392 (CH₂)₂ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1393 (CH₂)₃ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1394 (CH₂)₄ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1395 (CH₂)₅ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1396 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-trifluoro- hexane methoxyphenyl 1397 Cyclopentyl H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1398 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1399 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1400 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1401 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1402 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1403 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1404 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1405 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1406 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1407 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1408 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methylphenyl 1409 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1410 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1411 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1412 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1413 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1414 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 1415 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 1416 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1417 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1418 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1419 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1420 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-tolyl hexane 1421 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1422 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1423 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1424 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1425 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1426 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 1427 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 1428 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1429 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1430 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1431 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1432 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl hexane 1433 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1434 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1435 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1436 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1437 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1438 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 1439 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 1440 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1441 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1442 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1443 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1444 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-isopropyl- hexane phenyl 1445 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1446 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1447 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1448 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1449 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1450 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 1451 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 1452 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1453 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1454 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1455 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1456 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- hexane phenyl 1457 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1458 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1459 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1460 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1461 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1462 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 1463 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 1464 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1465 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1466 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1467 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1468 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 1469 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1470 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1471 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1472 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1473 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1474 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1475 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1476 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1477 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1478 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1479 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1480 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methylphenyl 1481 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1482 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1483 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1484 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1485 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1486 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 1487 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 1488 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1489 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1490 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1491 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1492 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-tolyl hexane 1493 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1494 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1495 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1496 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1497 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1498 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 1499 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 1500 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1501 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1502 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1503 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1504 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl hexane 1505 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1506 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1507 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1508 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1509 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1510 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 1511 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 1512 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1513 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1514 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1515 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1516 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- hexane phenyl 1517 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1518 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1519 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1520 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1521 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1522 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 1523 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 1524 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1525 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1526 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1527 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1528 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- hexane phenyl 1529 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1530 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1531 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1532 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1533 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 1534 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 1535 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1536 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1537 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1538 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1539 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 1540 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl

TABLE 5 Compounds of Formula IV Formula IV

Ex R1 R2 X R3 R5 Z 1541 CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 1542 CH₂CF₃ H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 1543 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 1544 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 1545 cyclopropyl- H O CH₂CF₃ CF₃ 4-trifluoro- methyl methylphenyl 1546 cyclobutyl- H O CH₂CF₃ CF₃ 4-trifluoro- methyl methylphenyl 1547 (CH₂)₂ O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 1548 (CH₂)₃ O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 1549 (CH₂)₄ O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 1550 (CH₂)₅ O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 1551 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-trifluoro- hexane methylphenyl 1552 Cyclopentyl H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 1553 CH₂CH₃ H O CH₂CF₃ CF₃ 4-tolyl 1554 CH₂CF₃ H O CH₂CF₃ CF₃ 4-tolyl 1555 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-tolyl 1556 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-tolyl 1557 cyclopropyl- H O CH₂CF₃ CF₃ 4-tolyl methyl 1558 cyclobutyl- H O CH₂CF₃ CF₃ 4-tolyl methyl 1559 (CH₂)₂ O CH₂CF₃ CF₃ 4-tolyl 1560 (CH₂)₃ O CH₂CF₃ CF₃ 4-tolyl 1561 (CH₂)₄ O CH₂CF₃ CF₃ 4-tolyl 1562 (CH₂)₅ O CH₂CF₃ CF₃ 4-tolyl 1563 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-tolyl hexane 1564 Cyclopentyl H O CH₂CF₃ CF₃ 4-tolyl 1565 CH₂CH₃ H O CH₂CF₃ CF₃ 4-ethylphenyl 1566 CH₂CF₃ H O CH₂CF₃ CF₃ 4-ethylphenyl 1567 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-ethylphenyl 1568 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-ethylphenyl 1569 cyclopropyl- H O CH₂CF₃ CF₃ 4-ethylphenyl methyl 1570 cyclobutyl- H O CH₂CF₃ CF₃ 4-ethylphenyl methyl 1571 (CH₂)₂ O CH₂CF₃ CF₃ 4-ethylphenyl 1572 (CH₂)₃ O CH₂CF₃ CF₃ 4-ethylphenyl 1573 (CH₂)₄ O CH₂CF₃ CF₃ 4-ethylphenyl 1574 (CH₂)₅ O CH₂CF₃ CF₃ 4-ethylphenyl 1575 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-ethylphenyl hexane 1576 Cyclopentyl H O CH₂CF₃ CF₃ 4-ethylphenyl 1577 CH₂CH₃ H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 1578 CH₂CF₃ H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 1579 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 1580 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 1581 cyclopropyl- H O CH₂CF₃ CF₃ 4-isopropyl- methyl phenyl 1582 cyclobutyl- H O CH₂CF₃ CF₃ 4-isopropyl- methyl phenyl 1583 (CH₂)₂ O CH₂CF₃ CF₃ 4-isopropyl- phenyl 1584 (CH₂)₃ O CH₂CF₃ CF₃ 4-isopropyl- phenyl 1585 (CH₂)₄ O CH₂CF₃ CF₃ 4-isopropyl- phenyl 1586 (CH₂)₅ O CH₂CF₃ CF₃ 4-isopropyl- phenyl 1587 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-isopropyl- hexane phenyl 1588 Cyclopentyl H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 1589 CH₂CH₃ H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 1590 CH₂CF₃ H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 1591 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 1592 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 1593 cyclopropyl- H O CH₂CF₃ CF₃ 4-thiomethyl- methyl phenyl 1594 cyclobutyl- H O CH₂CF₃ CF₃ 4-thiomethyl- methyl phenyl 1595 (CH₂)₂ O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 1596 (CH₂)₃ O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 1597 (CH₂)₄ O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 1598 (CH₂)₅ O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 1599 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-thiomethyl- hexane phenyl 1600 Cyclopentyl H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 1601 CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 1602 CH₂CF₃ H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 1603 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 1604 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 1605 cyclopropyl- H O CH₂CF₃ CF₃ 4-trifluoro- methyl methoxyphenyl 1606 cyclobutyl- H O CH₂CF₃ CF₃ 4-trifluoro- methyl methoxyphenyl 1607 (CH₂)₂ O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 1608 (CH₂)₃ O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 1609 (CH₂)₄ O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 1610 (CH₂)₅ O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 1611 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-trifluoro- hexane methoxyphenyl 1612 Cyclopentyl H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 1613 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 1614 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 1615 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 1616 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 1617 cyclopropyl- H O CH₂-c-Pr CF₃ 4-trifluoro- methyl methylphenyl 1618 cyclobutyl- H O CH₂-c-Pr CF₃ 4-trifluoro- methyl methylphenyl 1619 (CH₂)₂ O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 1620 (CH₂)₃ O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 1621 (CH₂)₄ O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 1622 (CH₂)₅ O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 1623 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-trifluoro- hexane methylphenyl 1624 Cyclopentyl H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 1625 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 1626 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-tolyl 1627 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 1628 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-tolyl 1629 cyclopropyl- H O CH₂-c-Pr CF₃ 4-tolyl methyl 1630 cyclobutyl- H O CH₂-c-Pr CF₃ 4-tolyl methyl 1631 (CH₂)₂ O CH₂-c-Pr CF₃ 4-tolyl 1632 (CH₂)₃ O CH₂-c-Pr CF₃ 4-tolyl 1633 (CH₂)₄ O CH₂-c-Pr CF₃ 4-tolyl 1634 (CH₂)₅ O CH₂-c-Pr CF₃ 4-tolyl 1635 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-tolyl hexane 1636 Cyclopentyl H O CH₂-c-Pr CF₃ 4-tolyl 1637 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-ethylphenyl 1638 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-ethylphenyl 1639 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-ethylphenyl 1640 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-ethylphenyl 1641 cyclopropyl- H O CH₂-c-Pr CF₃ 4-ethylphenyl methyl 1642 cyclobutyl- H O CH₂-c-Pr CF₃ 4-ethylphenyl methyl 1643 (CH₂)₂ O CH₂-c-Pr CF₃ 4-ethylphenyl 1644 (CH₂)₃ O CH₂-c-Pr CF₃ 4-ethylphenyl 1645 (CH₂)₄ O CH₂-c-Pr CF₃ 4-ethylphenyl 1646 (CH₂)₅ O CH₂-c-Pr CF₃ 4-ethylphenyl 1647 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-ethylphenyl hexane 1648 Cyclopentyl H O CH₂-c-Pr CF₃ 4-ethylphenyl 1649 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 1650 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 1651 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 1652 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 1653 cyclopropyl- H O CH₂-c-Pr CF₃ 4-isopropyl- methyl phenyl 1654 cyclobutyl- H O CH₂-c-Pr CF₃ 4-isopropyl- methyl phenyl 1655 (CH₂)₂ O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 1656 (CH₂)₃ O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 1657 (CH₂)₄ O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 1658 (CH₂)₅ O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 1659 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-isopropyl- hexane phenyl 1660 Cyclopentyl H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 1661 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 1662 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 1663 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 1664 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 1665 cyclopropyl- H O CH₂-c-Pr CF₃ 4-thiomethyl- methyl phenyl 1666 cyclobutyl- H O CH₂-c-Pr CF₃ 4-thiomethyl- methyl phenyl 1667 (CH₂)₂ O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 1668 (CH₂)₃ O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 1669 (CH₂)₄ O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 1670 (CH₂)₅ O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 1671 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-thiomethyl- hexane phenyl 1672 Cyclopentyl H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 1673 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 1674 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 1675 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 1676 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 1677 cyclopropyl- H O CH₂-c-Pr CF₃ 4-trifluoro- methyl methoxyphenyl 1678 cyclobutyl- H O CH₂-c-Pr CF₃ 4-trifluoro- methyl methoxyphenyl 1679 (CH₂)₂ O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 1680 (CH₂)₃ O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 1681 (CH₂)₄ O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 1682 (CH₂)₅ O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 1683 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-trifluoro- hexane methoxyphenyl 1684 Cyclopentyl H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 1685 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1686 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1687 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1688 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1689 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1690 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1691 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1692 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1693 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1694 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1695 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methylphenyl 1696 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1697 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1698 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1699 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1700 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1701 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 1702 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 1703 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1704 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1705 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1706 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1707 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-tolyl hexane 1708 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1709 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1710 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1711 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1712 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1713 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 1714 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 1715 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1716 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1717 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1718 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1719 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl hexane 1720 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1721 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1722 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1723 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1724 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1725 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 1726 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 1727 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1728 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1729 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1730 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1731 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-isopropyl- hexane phenyl 1732 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 1733 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1734 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1735 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1736 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1737 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 1738 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 1739 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1740 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1741 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1742 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1743 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- hexane phenyl 1744 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 1745 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1746 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1747 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1748 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1749 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 1750 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 1751 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1752 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1753 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1754 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1755 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 1756 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 1757 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1758 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1759 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1760 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1761 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1762 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1763 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1764 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1765 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1766 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1767 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methylphenyl 1768 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 1769 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1770 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1771 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1772 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1773 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 1774 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 1775 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1776 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1777 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1778 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1779 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-tolyl hexane 1780 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1781 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1782 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1783 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1784 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1785 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 1786 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 1787 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1788 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1789 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1790 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1791 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl hexane 1792 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 1793 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1794 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1795 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1796 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1797 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 1798 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 1799 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1800 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1801 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1802 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1803 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- hexane phenyl 1804 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 1805 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1806 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1807 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1808 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1809 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 1810 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 1811 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1812 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1813 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1814 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1815 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- hexane phenyl 1816 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 1817 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1818 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1819 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1820 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1821 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 1822 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 1823 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1824 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1825 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1826 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 1827 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 1828 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl

TABLE 6 Compounds of Formula IV Formula IV

Ex R1 R2 X R3 R5 Z 1829 CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1830 CH₂CF₃ H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1831 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1832 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1833 cyclopropyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methylphenyl 1834 cyclobutyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methylphenyl 1835 (CH₂)₂ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1836 (CH₂)₃ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1837 (CH₂)₄ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1838 (CH₂)₅ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1839 5,5-spiro[2.3] O CH₂CF₃ Cl 4-trifluoro- hexane methylphenyl 1840 Cyclopentyl H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 1841 CH₂CH₃ H O CH₂CF₃ Cl 4-tolyl 1842 CH₂CF₃ H O CH₂CF₃ Cl 4-tolyl 1843 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-tolyl 1844 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-tolyl 1845 cyclopropyl- H O CH₂CF₃ Cl 4-tolyl methyl 1846 cyclobutyl- H O CH₂CF₃ Cl 4-tolyl methyl 1847 (CH₂)₂ O CH₂CF₃ Cl 4-tolyl 1848 (CH₂)₃ O CH₂CF₃ Cl 4-tolyl 1849 (CH₂)₄ O CH₂CF₃ Cl 4-tolyl 1850 (CH₂)₅ O CH₂CF₃ Cl 4-tolyl 1851 5,5-spiro[2.3] O CH₂CF₃ Cl 4-tolyl hexane 1852 Cyclopentyl H O CH₂CF₃ Cl 4-tolyl 1853 CH₂CH₃ H O CH₂CF₃ Cl 4-ethylphenyl 1854 CH₂CF₃ H O CH₂CF₃ Cl 4-ethylphenyl 1855 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-ethylphenyl 1856 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-ethylphenyl 1857 cyclopropyl- H O CH₂CF₃ Cl 4-ethylphenyl methyl 1858 cyclobutyl- H O CH₂CF₃ Cl 4-ethylphenyl methyl 1859 (CH₂)₂ O CH₂CF₃ Cl 4-ethylphenyl 1860 (CH₂)₃ O CH₂CF₃ Cl 4-ethylphenyl 1861 (CH₂)₄ O CH₂CF₃ Cl 4-ethylphenyl 1862 (CH₂)₅ O CH₂CF₃ Cl 4-ethylphenyl 1863 5,5-spiro[2.3] O CH₂CF₃ Cl 4-ethylphenyl hexane 1864 Cyclopentyl H O CH₂CF₃ Cl 4-ethylphenyl 1865 CH₂CH₃ H O CH₂CF₃ Cl 4-isopropyl- phenyl 1866 CH₂CF₃ H O CH₂CF₃ Cl 4-isopropyl- phenyl 1867 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-isopropyl- phenyl 1868 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-isopropyl- phenyl 1869 cyclopropyl- H O CH₂CF₃ Cl 4-isopropyl- methyl phenyl 1870 cyclobutyl- H O CH₂CF₃ Cl 4-isopropyl- methyl phenyl 1871 (CH₂)₂ O CH₂CF₃ Cl 4-isopropyl- phenyl 1872 (CH₂)₃ O CH₂CF₃ Cl 4-isopropyl- phenyl 1873 (CH₂)₄ O CH₂CF₃ Cl 4-isopropyl- phenyl 1874 (CH₂)₅ O CH₂CF₃ Cl 4-isopropyl- phenyl 1875 5,5-spiro[2.3] O CH₂CF₃ Cl 4-isopropyl- hexane phenyl 1876 Cyclopentyl H O CH₂CF₃ Cl 4-isopropyl- phenyl 1877 CH₂CH₃ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1878 CH₂CF₃ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1879 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1880 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1881 cyclopropyl- H O CH₂CF₃ Cl 4-thiomethyl- methyl phenyl 1882 cyclobutyl- H O CH₂CF₃ Cl 4-thiomethyl- methyl phenyl 1883 (CH₂)₂ O CH₂CF₃ Cl 4-thiomethyl- phenyl 1884 (CH₂)₃ O CH₂CF₃ Cl 4-thiomethyl- phenyl 1885 (CH₂)₄ O CH₂CF₃ Cl 4-thiomethyl- phenyl 1886 (CH₂)₅ O CH₂CF₃ Cl 4-thiomethyl- phenyl 1887 5,5-spiro[2.3] O CH₂CF₃ Cl 4-thiomethyl- hexane phenyl 1888 Cyclopentyl H O CH₂CF₃ Cl 4-thiomethyl- phenyl 1889 CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1890 CH₂CF₃ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1891 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1892 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1893 cyclopropyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methoxyphenyl 1894 cyclobutyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methoxyphenyl 1895 (CH₂)₂ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1896 (CH₂)₃ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1897 (CH₂)₄ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1898 (CH₂)₅ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1899 5,5-spiro[2.3] O CH₂CF₃ Cl 4-trifluoro- hexane methoxyphenyl 1900 Cyclopentyl H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 1901 CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1902 CH₂CF₃ H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1903 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1904 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1905 cyclopropyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methylphenyl 1906 cyclobutyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methylphenyl 1907 (CH₂)₂ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1908 (CH₂)₃ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1909 (CH₂)₄ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1910 (CH₂)₅ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1911 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-trifluoro- hexane methylphenyl 1912 Cyclopentyl H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 1913 CH₂CH₃ H O CH₂-c-Pr Cl 4-tolyl 1914 CH₂CF₃ H O CH₂-c-Pr Cl 4-tolyl 1915 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-tolyl 1916 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-tolyl 1917 cyclopropyl- H O CH₂-c-Pr Cl 4-tolyl methyl 1918 cyclobutyl- H O CH₂-c-Pr Cl 4-tolyl methyl 1919 (CH₂)₂ O CH₂-c-Pr Cl 4-tolyl 1920 (CH₂)₃ O CH₂-c-Pr Cl 4-tolyl 1921 (CH₂)₄ O CH₂-c-Pr Cl 4-tolyl 1922 (CH₂)₅ O CH₂-c-Pr Cl 4-tolyl 1923 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-tolyl hexane 1924 Cyclopentyl H O CH₂-c-Pr Cl 4-tolyl 1925 CH₂CH₃ H O CH₂-c-Pr Cl 4-ethylphenyl 1926 CH₂CF₃ H O CH₂-c-Pr Cl 4-ethylphenyl 1927 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-ethylphenyl 1928 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-ethylphenyl 1929 cyclopropyl- H O CH₂-c-Pr Cl 4-ethylphenyl methyl 1930 cyclobutyl- H O CH₂-c-Pr Cl 4-ethylphenyl methyl 1931 (CH₂)₂ O CH₂-c-Pr Cl 4-ethylphenyl 1932 (CH₂)₃ O CH₂-c-Pr Cl 4-ethylphenyl 1933 (CH₂)₄ O CH₂-c-Pr Cl 4-ethylphenyl 1934 (CH₂)₅ O CH₂-c-Pr Cl 4-ethylphenyl 1935 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-ethylphenyl hexane 1936 Cyclopentyl H O CH₂-c-Pr Cl 4-ethylphenyl 1937 CH₂CH₃ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1938 CH₂CF₃ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1939 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1940 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1941 cyclopropyl- H O CH₂-c-Pr Cl 4-isopropyl- methyl phenyl 1942 cyclobutyl- H O CH₂-c-Pr Cl 4-isopropyl- methyl phenyl 1943 (CH₂)₂ O CH₂-c-Pr Cl 4-isopropyl- phenyl 1944 (CH₂)₃ O CH₂-c-Pr Cl 4-isopropyl- phenyl 1945 (CH₂)₄ O CH₂-c-Pr Cl 4-isopropyl- phenyl 1946 (CH₂)₅ O CH₂-c-Pr Cl 4-isopropyl- phenyl 1947 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-isopropyl- hexane phenyl 1948 Cyclopentyl H O CH₂-c-Pr Cl 4-isopropyl- phenyl 1949 CH₂CH₃ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1950 CH₂CF₃ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1951 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1952 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1953 cyclopropyl- H O CH₂-c-Pr Cl 4-thiomethyl- methyl phenyl 1954 cyclobutyl- H O CH₂-c-Pr Cl 4-thiomethyl- methyl phenyl 1955 (CH₂)₂ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1956 (CH₂)₃ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1957 (CH₂)₄ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1958 (CH₂)₅ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1959 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-thiomethyl- hexane phenyl 1960 Cyclopentyl H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 1961 CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1962 CH₂CF₃ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1963 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1964 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1965 cyclopropyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1966 cyclobutyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1967 (CH₂)₂ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1968 (CH₂)₃ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1969 (CH₂)₄ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1970 (CH₂)₅ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1971 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-trifluoro- hexane methoxyphenyl 1972 Cyclopentyl H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 1973 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1974 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1975 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1976 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1977 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1978 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 1979 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1980 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1981 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1982 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1983 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methylphenyl 1984 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 1985 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1986 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1987 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1988 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1989 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 1990 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 1991 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1992 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1993 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1994 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-tolyl 1995 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-tolyl hexane 1996 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-tolyl 1997 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1998 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 1999 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2000 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2001 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 2002 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 2003 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2004 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2005 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2006 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2007 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl hexane 2008 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2009 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2010 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2011 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2012 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2013 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 2014 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 2015 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2016 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2017 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2018 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2019 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-isopropyl- hexane phenyl 2020 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2031 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2032 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2033 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2034 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2035 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 2036 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 2037 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2038 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2039 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2040 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2041 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- hexane phenyl 2042 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2043 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2044 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2045 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2046 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2047 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2048 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2049 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2050 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2051 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2052 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2053 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 2054 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2055 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2056 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2057 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2058 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2059 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2060 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2061 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2062 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2063 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2064 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2065 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methylphenyl 2066 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2067 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2068 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2069 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2070 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2071 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 2072 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 2073 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2074 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2075 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2076 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2077 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-tolyl hexane 2078 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2079 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2080 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2081 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2082 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2083 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 2084 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 2085 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2086 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2087 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2088 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2089 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl hexane 2090 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2091 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2092 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2093 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2094 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2095 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 2096 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 2097 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2098 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2099 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2100 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2101 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- hexane phenyl 2102 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2103 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2104 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2105 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2106 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2107 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 2108 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 2109 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2110 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2111 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2112 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2113 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- hexane phenyl 2114 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2115 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2116 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2117 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2118 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2119 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2120 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2121 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2122 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2123 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2124 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2125 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 2126 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl

TABLE 7 Compounds of Formula VII Formula VII

Ex R1 R2 Y R4 R5 Z 2127 CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 2128 CH₂CF₃ H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 2129 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 2130 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 2131 cyclopropyl- H O CH₂CF₃ CF₃ 4-trifluoro- methyl methylphenyl 2132 cyclobutyl- H O CH₂CF₃ CF₃ 4-trifluoro- methyl methylphenyl 2133 (CH₂)₂ O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 2134 (CH₂)₃ O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 2135 (CH₂)₄ O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 2136 (CH₂)₅ O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 2137 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-trifluoro- hexane methylphenyl 2138 Cyclopentyl H O CH₂CF₃ CF₃ 4-trifluoro- methylphenyl 2139 CH₂CH₃ H O CH₂CF₃ CF₃ 4-tolyl 2140 CH₂CF₃ H O CH₂CF₃ CF₃ 4-tolyl 2141 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-tolyl 2142 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-tolyl 2143 cyclopropyl- H O CH₂CF₃ CF₃ 4-tolyl methyl 2144 cyclobutyl- H O CH₂CF₃ CF₃ 4-tolyl methyl 2145 (CH₂)₂ O CH₂CF₃ CF₃ 4-tolyl 2146 (CH₂)₃ O CH₂CF₃ CF₃ 4-tolyl 2147 (CH₂)₄ O CH₂CF₃ CF₃ 4-tolyl 2148 (CH₂)₅ O CH₂CF₃ CF₃ 4-tolyl 2149 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-tolyl hexane 2150 Cyclopentyl H O CH₂CF₃ CF₃ 4-tolyl 2151 CH₂CH₃ H O CH₂CF₃ CF₃ 4-ethylphenyl 2152 CH₂CF₃ H O CH₂CF₃ CF₃ 4-ethylphenyl 2153 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-ethylphenyl 2154 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-ethylphenyl 2155 cyclopropyl- H O CH₂CF₃ CF₃ 4-ethylphenyl methyl 2156 cyclobutyl- H O CH₂CF₃ CF₃ 4-ethylphenyl methyl 2157 (CH₂)₂ O CH₂CF₃ CF₃ 4-ethylphenyl 2158 (CH₂)₃ O CH₂CF₃ CF₃ 4-ethylphenyl 2159 (CH₂)₄ O CH₂CF₃ CF₃ 4-ethylphenyl 2160 (CH₂)₅ O CH₂CF₃ CF₃ 4-ethylphenyl 2161 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-ethylphenyl hexane 2162 Cyclopentyl H O CH₂CF₃ CF₃ 4-ethylphenyl 2163 CH₂CH₃ H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 2164 CH₂CF₃ H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 2165 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 2166 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 2167 cyclopropyl- H O CH₂CF₃ CF₃ 4-isopropyl- methyl phenyl 2168 cyclobutyl- H O CH₂CF₃ CF₃ 4-isopropyl- methyl phenyl 2169 (CH₂)₂ O CH₂CF₃ CF₃ 4-isopropyl- phenyl 2170 (CH₂)₃ O CH₂CF₃ CF₃ 4-isopropyl- phenyl 2171 (CH₂)₄ O CH₂CF₃ CF₃ 4-isopropyl- phenyl 2172 (CH₂)₅ O CH₂CF₃ CF₃ 4-isopropyl- phenyl 2173 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-isopropyl- hexane phenyl 2174 Cyclopentyl H O CH₂CF₃ CF₃ 4-isopropyl- phenyl 2175 CH₂CH₃ H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 2176 CH₂CF₃ H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 2177 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 2178 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 2179 cyclopropyl- H O CH₂CF₃ CF₃ 4-thiomethyl- methyl phenyl 2180 cyclobutyl- H O CH₂CF₃ CF₃ 4-thiomethyl- methyl phenyl 2181 (CH₂)₂ O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 2182 (CH₂)₃ O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 2183 (CH₂)₄ O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 2184 (CH₂)₅ O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 2185 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-thiomethyl- hexane phenyl 2186 Cyclopentyl H O CH₂CF₃ CF₃ 4-thiomethyl- phenyl 2187 CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 2188 CH₂CF₃ H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 2189 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 2190 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 2191 cyclopropyl- H O CH₂CF₃ CF₃ 4-trifluoro- methyl methoxyphenyl 2192 cyclobutyl- H O CH₂CF₃ CF₃ 4-trifluoro- methyl methoxyphenyl 2193 (CH₂)₂ O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 2194 (CH₂)₃ O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 2195 (CH₂)₄ O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 2196 (CH₂)₅ O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 2197 5,5-spiro[2.3] O CH₂CF₃ CF₃ 4-trifluoro- hexane methoxyphenyl 2198 Cyclopentyl H O CH₂CF₃ CF₃ 4-trifluoro- methoxyphenyl 2199 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 2200 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 2201 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 2202 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 2203 cyclopropyl- H O CH₂-c-Pr CF₃ 4-trifluoro- methyl methylphenyl 2204 cyclobutyl- H O CH₂-c-Pr CF₃ 4-trifluoro- methyl methylphenyl 2205 (CH₂)₂ O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 2206 (CH₂)₃ O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 2207 (CH₂)₄ O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 2208 (CH₂)₅ O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 2209 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-trifluoro- hexane methylphenyl 2210 Cyclopentyl H O CH₂-c-Pr CF₃ 4-trifluoro- methylphenyl 2211 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 2212 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-tolyl 2213 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 2214 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-tolyl 2215 cyclopropyl- H O CH₂-c-Pr CF₃ 4-tolyl methyl 2216 cyclobutyl- H O CH₂-c-Pr CF₃ 4-tolyl methyl 2217 (CH₂)₂ O CH₂-c-Pr CF₃ 4-tolyl 2218 (CH₂)₃ O CH₂-c-Pr CF₃ 4-tolyl 2219 (CH₂)₄ O CH₂-c-Pr CF₃ 4-tolyl 2220 (CH₂)₅ O CH₂-c-Pr CF₃ 4-tolyl 2221 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-tolyl hexane 2222 Cyclopentyl H O CH₂-c-Pr CF₃ 4-tolyl 2223 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-ethylphenyl 2224 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-ethylphenyl 2225 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-ethylphenyl 2226 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-ethylphenyl 2227 cyclopropyl- H O CH₂-c-Pr CF₃ 4-ethylphenyl methyl 2228 cyclobutyl- H O CH₂-c-Pr CF₃ 4-ethylphenyl methyl 2229 (CH₂)₂ O CH₂-c-Pr CF₃ 4-ethylphenyl 2230 (CH₂)₃ O CH₂-c-Pr CF₃ 4-ethylphenyl 2231 (CH₂)₄ O CH₂-c-Pr CF₃ 4-ethylphenyl 2232 (CH₂)₅ O CH₂-c-Pr CF₃ 4-ethylphenyl 2233 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-ethylphenyl hexane 2234 Cyclopentyl H O CH₂-c-Pr CF₃ 4-ethylphenyl 2235 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 2236 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 2237 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 2238 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 2239 cyclopropyl- H O CH₂-c-Pr CF₃ 4-isopropyl- methyl phenyl 2240 cyclobutyl- H O CH₂-c-Pr CF₃ 4-isopropyl- methyl phenyl 2241 (CH₂)₂ O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 2242 (CH₂)₃ O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 2243 (CH₂)₄ O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 2244 (CH₂)₅ O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 2245 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-isopropyl- hexane phenyl 2246 Cyclopentyl H O CH₂-c-Pr CF₃ 4-isopropyl- phenyl 2247 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 2248 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 2249 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 2250 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 2251 cyclopropyl- H O CH₂-c-Pr CF₃ 4-thiomethyl- methyl phenyl 2252 cyclobutyl- H O CH₂-c-Pr CF₃ 4-thiomethyl- methyl phenyl 2253 (CH₂)₂ O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 2254 (CH₂)₃ O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 2255 (CH₂)₄ O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 2256 (CH₂)₅ O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 2257 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-thiomethyl- hexane phenyl 2258 Cyclopentyl H O CH₂-c-Pr CF₃ 4-thiomethyl- phenyl 2259 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 2260 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 2261 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 2262 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 2263 cyclopropyl- H O CH₂-c-Pr CF₃ 4-trifluoro- methyl methoxyphenyl 2264 cyclobutyl- H O CH₂-c-Pr CF₃ 4-trifluoro- methyl methoxyphenyl 2265 (CH₂)₂ O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 2266 (CH₂)₃ O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 2267 (CH₂)₄ O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 2268 (CH₂)₅ O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 2269 5,5-spiro[2.3] O CH₂-c-Pr CF₃ 4-trifluoro- hexane methoxyphenyl 2270 Cyclopentyl H O CH₂-c-Pr CF₃ 4-trifluoro- methoxyphenyl 2271 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2272 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2273 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2274 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2275 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2276 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2277 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2278 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2279 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2280 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2281 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methylphenyl 2282 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2283 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2284 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2285 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2286 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2287 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 2288 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 2289 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-tolyl 2290 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-tolyl 2291 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-tolyl 2292 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-tolyl 2293 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-tolyl hexane 2294 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2295 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2296 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2297 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2298 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2299 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 2300 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 2301 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2302 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2303 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2304 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2305 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl hexane 2306 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2307 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2308 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2309 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2310 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2311 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 2312 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 2313 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2314 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2315 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2316 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2317 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-isopropyl- hexane phenyl 2318 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2319 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2320 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2321 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2322 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2323 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 2324 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 2325 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2326 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2327 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2328 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2329 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- hexane phenyl 2330 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2331 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2332 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2333 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2334 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2335 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2336 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2337 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2338 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2339 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2340 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2341 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 2342 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2343 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2344 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2345 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2346 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2347 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2348 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2349 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2350 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2351 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2352 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2353 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methylphenyl 2354 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2355 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2356 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2357 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2358 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2359 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 2360 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 2361 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2362 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2363 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2364 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2365 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-tolyl hexane 2366 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2367 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2368 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2369 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2370 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2371 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 2372 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 2373 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2374 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2375 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2376 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2377 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl hexane 2378 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2379 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2380 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2381 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2382 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2383 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 2384 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 2385 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2386 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2386 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2388 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2389 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- hexane phenyl 2390 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2391 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2392 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2393 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2394 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2395 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 2396 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 2397 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2398 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2399 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2400 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2401 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- hexane phenyl 2402 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2403 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2404 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2405 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2406 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2407 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2408 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2409 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2410 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2411 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2412 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2413 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 2414 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl

TABLE 8 Compounds of Formula VII Formula VII

Ex R1 R2 Y R4 R5 Z 2415 CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 2416 CH₂CF₃ H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 2417 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 2418 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 2419 cyclopropyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methylphenyl 2420 cyclobutyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methylphenyl 2421 (CH₂)₂ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 2422 (CH₂)₃ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 2423 (CH₂)₄ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 2424 (CH₂)₅ O CH₂CF₃ Cl 4-trifluoro- methylphenyl 2425 5,5-spiro[2.3] O CH₂CF₃ Cl 4-trifluoro- hexane methylphenyl 2426 Cyclopentyl H O CH₂CF₃ Cl 4-trifluoro- methylphenyl 2427 CH₂CH₃ H O CH₂CF₃ Cl 4-tolyl 2428 CH₂CF₃ H O CH₂CF₃ Cl 4-tolyl 2429 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-tolyl 2430 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-tolyl 2431 cyclopropyl- H O CH₂CF₃ Cl 4-tolyl methyl 2432 cyclobutyl- H O CH₂CF₃ Cl 4-tolyl methyl 2433 (CH₂)₂ O CH₂CF₃ Cl 4-tolyl 2434 (CH₂)₃ O CH₂CF₃ Cl 4-tolyl 2435 (CH₂)₄ O CH₂CF₃ Cl 4-tolyl 2436 (CH₂)₅ O CH₂CF₃ Cl 4-tolyl 2437 5,5-spiro[2.3] O CH₂CF₃ Cl 4-tolyl hexane 2438 Cyclopentyl H O CH₂CF₃ Cl 4-tolyl 2439 CH₂CH₃ H O CH₂CF₃ Cl 4-ethylphenyl 2440 CH₂CF₃ H O CH₂CF₃ Cl 4-ethylphenyl 2441 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-ethylphenyl 2442 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-ethylphenyl 2443 cyclopropyl- H O CH₂CF₃ Cl 4-ethylphenyl methyl 2444 cyclobutyl- H O CH₂CF₃ Cl 4-ethylphenyl methyl 2445 (CH₂)₂ O CH₂CF₃ Cl 4-ethylphenyl 2446 (CH₂)₃ O CH₂CF₃ Cl 4-ethylphenyl 2447 (CH₂)₄ O CH₂CF₃ Cl 4-ethylphenyl 2448 (CH₂)₅ O CH₂CF₃ Cl 4-ethylphenyl 2449 5,5-spiro[2.3] O CH₂CF₃ Cl 4-ethylphenyl hexane 2450 Cyclopentyl H O CH₂CF₃ Cl 4-ethylphenyl 2451 CH₂CH₃ H O CH₂CF₃ Cl 4-isopropyl- phenyl 2452 CH₂CF₃ H O CH₂CF₃ Cl 4-isopropyl- phenyl 2453 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-isopropyl- phenyl 2454 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-isopropyl- phenyl 2455 cyclopropyl- H O CH₂CF₃ Cl 4-isopropyl- methyl phenyl 2456 cyclobutyl- H O CH₂CF₃ Cl 4-isopropyl- methyl phenyl 2457 (CH₂)₂ O CH₂CF₃ Cl 4-isopropyl- phenyl 2458 (CH₂)₃ O CH₂CF₃ Cl 4-isopropyl- phenyl 2459 (CH₂)₄ O CH₂CF₃ Cl 4-isopropyl- phenyl 2460 (CH₂)₅ O CH₂CF₃ Cl 4-isopropyl- phenyl 2461 5,5-spiro[2.3] O CH₂CF₃ Cl 4-isopropyl- hexane phenyl 2462 Cyclopentyl H O CH₂CF₃ Cl 4-isopropyl- phenyl 2463 CH₂CH₃ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 2464 CH₂CF₃ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 2465 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 2466 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-thiomethyl- phenyl 2467 cyclopropyl- H O CH₂CF₃ Cl 4-thiomethyl- methyl phenyl 2468 cyclobutyl- H O CH₂CF₃ Cl 4-thiomethyl- methyl phenyl 2469 (CH₂)₂ O CH₂CF₃ Cl 4-thiomethyl- phenyl 2470 (CH₂)₃ O CH₂CF₃ Cl 4-thiomethyl- phenyl 2471 (CH₂)₄ O CH₂CF₃ Cl 4-thiomethyl- phenyl 2472 (CH₂)₅ O CH₂CF₃ Cl 4-thiomethyl- phenyl 2473 5,5-spiro[2.3] O CH₂CF₃ Cl 4-thiomethyl- hexane phenyl 2474 Cyclopentyl H O CH₂CF₃ Cl 4-thiomethyl- phenyl 2475 CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 2476 CH₂CF₃ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 2477 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 2478 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 2479 cyclopropyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methoxyphenyl 2480 cyclobutyl- H O CH₂CF₃ Cl 4-trifluoro- methyl methoxyphenyl 2481 (CH₂)₂ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 2482 (CH₂)₃ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 2483 (CH₂)₄ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 2484 (CH₂)₅ O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 2485 5,5-spiro[2.3] O CH₂CF₃ Cl 4-trifluoro- hexane methoxyphenyl 2486 Cyclopentyl H O CH₂CF₃ Cl 4-trifluoro- methoxyphenyl 2487 CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 2488 CH₂CF₃ H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 2489 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 2490 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 2491 cyclopropyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methylphenyl 2492 cyclobutyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methylphenyl 2493 (CH₂)₂ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 2494 (CH₂)₃ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 2495 (CH₂)₄ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 2496 (CH₂)₅ O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 2497 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-trifluoro- hexane methylphenyl 2498 Cyclopentyl H O CH₂-c-Pr Cl 4-trifluoro- methylphenyl 2499 CH₂CH₃ H O CH₂-c-Pr Cl 4-tolyl 2500 CH₂CF₃ H O CH₂-c-Pr Cl 4-tolyl 2501 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-tolyl 2502 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-tolyl 2503 cyclopropyl- H O CH₂-c-Pr Cl 4-tolyl methyl 2504 cyclobutyl- H O CH₂-c-Pr Cl 4-tolyl methyl 2505 (CH₂)₂ O CH₂-c-Pr Cl 4-tolyl 2506 (CH₂)₃ O CH₂-c-Pr Cl 4-tolyl 2507 (CH₂)₄ O CH₂-c-Pr Cl 4-tolyl 2508 (CH₂)₅ O CH₂-c-Pr Cl 4-tolyl 2509 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-tolyl hexane 2510 Cyclopentyl H O CH₂-c-Pr Cl 4-tolyl 2511 CH₂CH₃ H O CH₂-c-Pr Cl 4-ethylphenyl 2512 CH₂CF₃ H O CH₂-c-Pr Cl 4-ethylphenyl 2513 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-ethylphenyl 2514 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-ethylphenyl 2515 cyclopropyl- H O CH₂-c-Pr Cl 4-ethylphenyl methyl 2516 cyclobutyl- H O CH₂-c-Pr Cl 4-ethylphenyl methyl 2517 (CH₂)₂ O CH₂-c-Pr Cl 4-ethylphenyl 2518 (CH₂)₃ O CH₂-c-Pr Cl 4-ethylphenyl 2519 (CH₂)₄ O CH₂-c-Pr Cl 4-ethylphenyl 2520 (CH₂)₅ O CH₂-c-Pr Cl 4-ethylphenyl 2521 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-ethylphenyl hexane 2522 Cyclopentyl H O CH₂-c-Pr Cl 4-ethylphenyl 2523 CH₂CH₃ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 2524 CH₂CF₃ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 2525 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 2526 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-isopropyl- phenyl 2527 cyclopropyl- H O CH₂-c-Pr Cl 4-isopropyl- methyl phenyl 2528 cyclobutyl- H O CH₂-c-Pr Cl 4-isopropyl- methyl phenyl 2529 (CH₂)₂ O CH₂-c-Pr Cl 4-isopropyl- phenyl 2530 (CH₂)₃ O CH₂-c-Pr Cl 4-isopropyl- phenyl 2531 (CH₂)₄ O CH₂-c-Pr Cl 4-isopropyl- phenyl 2532 (CH₂)₅ O CH₂-c-Pr Cl 4-isopropyl- phenyl 2533 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-isopropyl- hexane phenyl 2534 Cyclopentyl H O CH₂-c-Pr Cl 4-isopropyl- phenyl 2535 CH₂CH₃ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 2536 CH₂CF₃ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 2537 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 2538 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 2539 cyclopropyl- H O CH₂-c-Pr Cl 4-thiomethyl- methyl phenyl 2540 cyclobutyl- H O CH₂-c-Pr Cl 4-thiomethyl- methyl phenyl 2541 (CH₂)₂ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 2542 (CH₂)₃ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 2543 (CH₂)₄ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 2544 (CH₂)₅ O CH₂-c-Pr Cl 4-thiomethyl- phenyl 2545 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-thiomethyl- hexane phenyl 2546 Cyclopentyl H O CH₂-c-Pr Cl 4-thiomethyl- phenyl 2547 CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 2548 CH₂CF₃ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 2549 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 2550 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 2551 cyclopropyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 2552 cyclobutyl- H O CH₂-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 2553 (CH₂)₂ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 2554 (CH₂)₃ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 2555 (CH₂)₄ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 2556 (CH₂)₅ O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 2557 5,5-spiro[2.3] O CH₂-c-Pr Cl 4-trifluoro- hexane methoxyphenyl 2558 Cyclopentyl H O CH₂-c-Pr Cl 4-trifluoro- methoxyphenyl 2559 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2560 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2561 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2562 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2563 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2564 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2565 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2566 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2567 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2568 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2569 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methylphenyl 2570 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methylphenyl 2571 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2572 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2573 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2574 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2575 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 2576 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-tolyl methyl 2577 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-tolyl 2578 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-tolyl 2579 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-tolyl 2580 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-tolyl 2581 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-tolyl hexane 2582 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-tolyl 2583 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2584 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2585 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2586 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2587 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 2588 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl methyl 2589 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2590 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2591 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2592 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2593 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl hexane 2594 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-ethylphenyl 2595 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2596 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2597 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2598 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2599 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 2600 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- methyl phenyl 2601 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2602 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2603 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2604 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2605 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-isopropyl- hexane phenyl 2606 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-isopropyl- phenyl 2607 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2608 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2609 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2610 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2611 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 2612 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- methyl phenyl 2613 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2614 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2615 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2616 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2617 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- hexane phenyl 2618 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-thiomethyl- phenyl 2619 CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2620 CH₂CF₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2621 CH₂CH₂CH₃ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2622 CH₂CH(CH₃)₂ H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2623 cyclopropyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2624 cyclobutyl- H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2625 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2626 (CH₂)₃ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2627 (CH₂)₄ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2628 (CH₂)₅ O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2629 5,5-spiro[2.3] O CH₂CF₃ OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 2630 Cyclopentyl H O CH₂CF₃ OCH₂CF₃ 4-trifluoro- methoxyphenyl 2632 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2633 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2634 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2635 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2636 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2637 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methylphenyl 2638 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2639 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2640 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2641 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2642 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methylphenyl 2643 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methylphenyl 2644 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2645 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2646 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2647 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2648 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 2649 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-tolyl methyl 2650 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2651 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2652 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2653 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2654 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-tolyl hexane 2655 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2656 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2657 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2658 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2659 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2660 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 2661 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl methyl 2662 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2663 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2664 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2665 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2666 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl hexane 2667 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-ethylphenyl 2668 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2669 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2670 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2671 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2672 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 2673 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- methyl phenyl 2674 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2675 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2676 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2677 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2678 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- hexane phenyl 2679 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl- phenyl 2680 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2681 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2682 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2683 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2684 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 2685 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- methyl phenyl 2686 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2687 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2688 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2689 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2690 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- hexane phenyl 2691 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-thiomethyl- phenyl 2692 CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2693 CH₂CF₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2694 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2695 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2696 cyclopropyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2697 cyclobutyl- H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methyl methoxyphenyl 2698 (CH₂)₂ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2699 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2700 (CH₂)₄ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2701 (CH₂)₅ O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl 2702 5,5-spiro[2.3] O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- hexane methoxyphenyl 2703 Cyclopentyl H O CH₂-c-Pr OCH₂CF₃ 4-trifluoro- methoxyphenyl

TABLE 9 Compounds of Formula III Formula III

Ex R1 R2 Y R4 R5 Z 2704 CH₂CH₃ H O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl 2705 CH₂CF₃ H O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl 2706 CH₂CH₂CH₃ H O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl 2707 CH₂CH(CH₃)₂ H O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl 2708 cyclopropyl- H O CH₂CH₂CF₃ Cl 4-trifluoro- methyl methylphenyl 2709 cyclobutyl- H O CH₂CH₂CF₃ Cl 4-trifluoro- methyl methylphenyl 2710 (CH₂)₂ O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl 2711 (CH₂)₃ O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl 2712 (CH₂)₄ O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl 2713 (CH₂)₅ O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl 2714 5,5-spiro[2.3]hexane O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl 2715 Cyclopentyl H O CH₂CH₂CF₃ Cl 4-trifluoro- methylphenyl

TABLE 10 Compounds of Formula III Formula III

Ex R1 R2 Y R4 R5 Z 2716 CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2717 CH₂CF₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2718 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2719 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2720 cyclopropyl- H O CH₂CF₃ CF₃ 5-benzo[c] methyl [1,2,5]oxadiazole 2721 cyclobutylmethyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2722 (CH₂)₂ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2723 (CH₂)₃ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2724 (CH₂)₄ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2725 (CH₂)₅ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2726 5,5-spiro[2.3]hexane O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2727 Cyclopentyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2733 cyclobutylmethyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2735 (CH₂)₃ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2737 (CH₂)₅ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2738 5,5-spiro[2.3]hexane O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2739 Cyclopentyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2745 cyclobutylmethyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2747 (CH₂)₃ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2749 (CH₂)₅ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2750 5,5-spiro[2.3]hexane O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2751 Cyclopentyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2752 CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2753 CH₂CF₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2754 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2755 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2756 cyclopropyl- H O CH₂CF₃ CF₃ 5-benzo[c] methyl [1,2,5]thiadiazole 2757 cyclobutylmethyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2758 (CH₂)₂ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2759 (CH₂)₃ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2760 (CH₂)₄ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2761 (CH₂)₅ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2762 5,5-spiro[2.3]hexane O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2763 Cyclopentyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2769 cyclobutylmethyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2771 (CH₂)₃ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2773 (CH₂)₅ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2774 5,5-spiro[2.3]hexane O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2775 Cyclopentyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2781 cyclobutylmethyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2783 (CH₂)₃ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2785 (CH₂)₅ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2786 5,5-spiro[2.3]hexane O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2787 Cyclopentyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2788 CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2789 CH₂CF₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2790 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2791 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2792 cyclopropyl- H O CH₂-c-Pr CF₃ 5-benzo[c] methyl [1,2,5]oxadiazole 2793 cyclobutylmethyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2794 (CH₂)₂ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2795 (CH₂)₃ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2796 (CH₂)₄ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2797 (CH₂)₅ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2798 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2799 Cyclopentyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2805 cyclobutylmethyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2807 (CH₂)₃ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2809 (CH₂)₅ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2810 5,5-spiro[2.3]hexane O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2811 Cyclopentyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2817 cyclobutylmethyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2819 (CH₂)₃ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2821 (CH₂)₅ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2822 5,5-spiro[2.3]hexane O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2823 Cyclopentyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2824 CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2825 CH₂CF₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2826 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2827 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2828 cyclopropyl- H O CH₂-c-Pr CF₃ 5-benzo[c] methyl [1,2,5]thiadiazole 2829 cyclobutylmethyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2830 (CH₂)₂ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2831 (CH₂)₃ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2832 (CH₂)₄ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2833 (CH₂)₅ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2834 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2835 Cyclopentyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2841 cyclobutylmethyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2843 (CH₂)₃ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2845 (CH₂)₅ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2846 5,5-spiro[2.3]hexane O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2847 Cyclopentyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2853 cyclobutylmethyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2855 (CH₂)₃ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2857 (CH₂)₅ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2858 5,5-spiro[2.3]hexane O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2859 Cyclopentyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole

TABLE 11 Compounds of Formula IV Formula IV

Ex R1 R2 X R3 R5 Z 2860 CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2861 CH₂CF₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2862 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2863 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2864 cyclopropyl- H O CH₂CF₃ CF₃ 5-benzo[c] methyl [1,2,5]oxadiazole 2865 cyclobutylmethyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2866 (CH₂)₂ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2867 (CH₂)₃ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2868 (CH₂)₄ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2869 (CH₂)₅ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2870 5,5-spiro[2.3]hexane O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2871 Cyclopentyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 2872 CH₂CH₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2873 CH₂CF₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2874 CH₂CH₂CH₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2875 CH₂CH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2876 cyclopropyl- H O CH₂CF₃ F 5-benzo[c] methyl [1,2,5]oxadiazole 2877 cyclobutylmethyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2878 (CH₂)₂ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2879 (CH₂)₃ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2880 (CH₂)₄ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2881 (CH₂)₅ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2882 5,5-spiro[2.3]hexane O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2883 Cyclopentyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 2884 CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2885 CH₂CF₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2886 CH₂CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2887 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2888 cyclopropyl- H O CH₂CF₃ Cl 5-benzo[c] methyl [1,2,5]oxadiazole 2889 cyclobutylmethyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2890 (CH₂)₂ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2891 (CH₂)₃ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2892 (CH₂)₄ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2893 (CH₂)₅ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2894 5,5-spiro[2.3]hexane O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2895 Cyclopentyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 2896 CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2897 CH₂CF₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2898 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2899 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2900 cyclopropyl- H O CH₂CF₃ CF₃ 5-benzo[c] methyl [1,2,5]thiadiazole 2901 cyclobutylmethyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2902 (CH₂)₂ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2903 (CH₂)₃ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2904 (CH₂)₄ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2905 (CH₂)₅ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2906 5,5-spiro[2.3]hexane O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2907 Cyclopentyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 2908 CH₂CH₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2909 CH₂CF₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2910 CH₂CH₂CH₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2911 CH₂CH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2912 cyclopropyl- H O CH₂CF₃ F 5-benzo[c] methyl [1,2,5]thiadiazole 2913 cyclobutylmethyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2914 (CH₂)₂ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2915 (CH₂)₃ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2916 (CH₂)₄ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2917 (CH₂)₅ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2918 5,5-spiro[2.3]hexane O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2919 Cyclopentyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 2920 CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2921 CH₂CF₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2922 CH₂CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2923 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2924 cyclopropyl- H O CH₂CF₃ Cl 5-benzo[c] methyl [1,2,5]thiadiazole 2925 cyclobutylmethyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2926 (CH₂)₂ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2927 (CH₂)₃ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2928 (CH₂)₄ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2929 (CH₂)₅ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2930 5,5-spiro[2.3]hexane O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2931 Cyclopentyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 2932 CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2933 CH₂CF₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2934 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2935 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2936 cyclopropyl- H O CH₂-c-Pr CF₃ 5-benzo[c] methyl [1,2,5]oxadiazole 2937 cyclobutylmethyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2938 (CH₂)₂ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2939 (CH₂)₃ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2940 (CH₂)₄ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2941 (CH₂)₅ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2942 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2943 Cyclopentyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 2944 CH₂CH₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2945 CH₂CF₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2946 CH₂CH₂CH₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2947 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2948 cyclopropyl- H O CH₂-c-Pr F 5-benzo[c] methyl [1,2,5]oxadiazole 2949 cyclobutylmethyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2950 (CH₂)₂ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2951 (CH₂)₃ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2952 (CH₂)₄ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2953 (CH₂)₅ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2954 5,5-spiro[2.3]hexane O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2955 Cyclopentyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 2956 CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2957 CH₂CF₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2958 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2959 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2960 cyclopropyl- H O CH₂-c-Pr Cl 5-benzo[c] methyl [1,2,5]oxadiazole 2961 cyclobutylmethyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2962 (CH₂)₂ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2963 (CH₂)₃ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2964 (CH₂)₄ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2965 (CH₂)₅ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2966 5,5-spiro[2.3]hexane O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2967 Cyclopentyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 2968 CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2969 CH₂CF₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2970 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2971 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2972 cyclopropyl- H O CH₂-c-Pr CF₃ 5-benzo[c] methyl [1,2,5]thiadiazole 2973 cyclobutylmethyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2974 (CH₂)₂ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2975 (CH₂)₃ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2976 (CH₂)₄ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2977 (CH₂)₅ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2978 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2979 Cyclopentyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 2980 CH₂CH₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2981 CH₂CF₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2982 CH₂CH₂CH₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2983 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2984 cyclopropyl- H O CH₂-c-Pr F 5-benzo[c] methyl [1,2,5]thiadiazole 2985 cyclobutylmethyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2986 (CH₂)₂ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2987 (CH₂)₃ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2988 (CH₂)₄ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2989 (CH₂)₅ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2990 5,5-spiro[2.3]hexane O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2991 Cyclopentyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 2992 CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2993 CH₂CF₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2994 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2995 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2996 cyclopropyl- H O CH₂-c-Pr Cl 5-benzo[c] methyl [1,2,5]thiadiazole 2997 cyclobutylmethyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2998 (CH₂)₂ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 2999 (CH₂)₃ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3000 (CH₂)₄ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3001 (CH₂)₅ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3002 5,5-spiro[2.3]hexane O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3003 Cyclopentyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole

TABLE 12 Compounds of Formula VII Formula VII

Ex R1 R2 Y R4 R5 Z 3004 CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3005 CH₂CF₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3006 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3007 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3008 cyclopropyl- H O CH₂CF₃ CF₃ 5-benzo[c] methyl [1,2,5]oxadiazole 3009 cyclobutylmethyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3010 (CH₂)₂ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3011 (CH₂)₃ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3012 (CH₂)₄ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3013 (CH₂)₅ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3014 5,5-spiro[2.3]hexane O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3015 Cyclopentyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]oxadiazole 3016 CH₂CH₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3017 CH₂CF₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3018 CH₂CH₂CH₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3019 CH₂CH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3020 cyclopropyl- H O CH₂CF₃ F 5-benzo[c] methyl [1,2,5]oxadiazole 3021 cyclobutylmethyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3022 (CH₂)₂ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3023 (CH₂)₃ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3024 (CH₂)₄ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3025 (CH₂)₅ O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3026 5,5-spiro[2.3]hexane O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3027 Cyclopentyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]oxadiazole 3028 CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3029 CH₂CF₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3030 CH₂CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3031 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3032 cyclopropyl- H O CH₂CF₃ Cl 5-benzo[c] methyl [1,2,5]oxadiazole 3033 cyclobutylmethyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3034 (CH₂)₂ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3035 (CH₂)₃ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3036 (CH₂)₄ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3037 (CH₂)₅ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3038 5,5-spiro[2.3]hexane O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3039 Cyclopentyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]oxadiazole 3040 CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3041 CH₂CF₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3042 CH₂CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3043 CH₂CH(CH₃)₂ H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3044 cyclopropyl- H O CH₂CF₃ CF₃ 5-benzo[c] methyl [1,2,5]thiadiazole 3045 cyclobutylmethyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3046 (CH₂)₂ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3047 (CH₂)₃ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3048 (CH₂)₄ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3049 (CH₂)₅ O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3050 5,5-spiro[2.3]hexane O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3051 Cyclopentyl H O CH₂CF₃ CF₃ 5-benzo[c] [1,2,5]thiadiazole 3052 CH₂CH₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3053 CH₂CF₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3054 CH₂CH₂CH₃ H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3055 CH₂CH(CH₃)₂ H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3056 cyclopropyl- H O CH₂CF₃ F 5-benzo[c] methyl [1,2,5]thiadiazole 3057 cyclobutylmethyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3058 (CH₂)₂ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3059 (CH₂)₃ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3060 (CH₂)₄ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3061 (CH₂)₅ O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3062 5,5-spiro[2.3]hexane O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3063 Cyclopentyl H O CH₂CF₃ F 5-benzo[c] [1,2,5]thiadiazole 3064 CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3065 CH₂CF₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3066 CH₂CH₂CH₃ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3067 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3068 cyclopropyl- H O CH₂CF₃ Cl 5-benzo[c] methyl [1,2,5]thiadiazole 3069 cyclobutylmethyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3070 (CH₂)₂ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3071 (CH₂)₃ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3072 (CH₂)₄ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3073 (CH₂)₅ O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3074 5,5-spiro[2.3]hexane O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3075 Cyclopentyl H O CH₂CF₃ Cl 5-benzo[c] [1,2,5]thiadiazole 3076 CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3077 CH₂CF₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3078 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3079 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3080 cyclopropyl- H O CH₂-c-Pr CF₃ 5-benzo[c] methyl [1,2,5]oxadiazole 3081 cyclobutylmethyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3082 (CH₂)₂ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3083 (CH₂)₃ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3084 (CH₂)₄ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3085 (CH₂)₅ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3086 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3087 Cyclopentyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]oxadiazole 3088 CH₂CH₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3089 CH₂CF₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3090 CH₂CH₂CH₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3091 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3092 cyclopropyl- H O CH₂-c-Pr F 5-benzo[c] methyl [1,2,5]oxadiazole 3093 cyclobutylmethyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3094 (CH₂)₂ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3095 (CH₂)₃ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3096 (CH₂)₄ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3097 (CH₂)₅ O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3098 5,5-spiro[2.3]hexane O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3099 Cyclopentyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]oxadiazole 3100 CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3101 CH₂CF₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3102 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3103 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3104 cyclopropyl- H O CH₂-c-Pr Cl 5-benzo[c] methyl [1,2,5]oxadiazole 3105 cyclobutylmethyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3106 (CH₂)₂ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3107 (CH₂)₃ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3108 (CH₂)₄ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3109 (CH₂)₅ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3110 5,5-spiro[2.3]hexane O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3111 Cyclopentyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]oxadiazole 3112 CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3113 CH₂CF₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3114 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3115 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3116 cyclopropyl- H O CH₂-c-Pr CF₃ 5-benzo[c] methyl [1,2,5]thiadiazole 3117 cyclobutylmethyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3118 (CH₂)₂ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3119 (CH₂)₃ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3120 (CH₂)₄ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3121 (CH₂)₅ O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3122 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3123 Cyclopentyl H O CH₂-c-Pr CF₃ 5-benzo[c] [1,2,5]thiadiazole 3124 CH₂CH₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3125 CH₂CF₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3126 CH₂CH₂CH₃ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3127 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3128 cyclopropyl- H O CH₂-c-Pr F 5-benzo[c] methyl [1,2,5]thiadiazole 3129 cyclobutylmethyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3130 (CH₂)₂ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3131 (CH₂)₃ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3132 (CH₂)₄ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3133 (CH₂)₅ O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3134 5,5-spiro[2.3]hexane O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3135 Cyclopentyl H O CH₂-c-Pr F 5-benzo[c] [1,2,5]thiadiazole 3136 CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3137 CH₂CF₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3138 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3139 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3140 cyclopropyl- H O CH₂-c-Pr Cl 5-benzo[c] methyl [1,2,5]thiadiazole 3141 cyclobutylmethyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3142 (CH₂)₂ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3143 (CH₂)₃ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3144 (CH₂)₄ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3145 (CH₂)₅ O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3146 5,5-spiro[2.3]hexane O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole 3147 Cyclopentyl H O CH₂-c-Pr Cl 5-benzo[c] [1,2,5]thiadiazole

EXPERIMENTAL PROCEDURES Example 534 2-(6-cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 2-(3-Bromo-4-hydroxyphenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)-4-methylpentanoate E-9 (15 g, 63.55 mmol) in 100 ml of glacial acetic acid at 0° C., slowly added bromine (20.26 g, 64.14 mol) and stirred at same temperature for 2.5 h. After completion the reaction, the reaction mixture was poured into water and neutralized with saturated sodium carbonate solution and extracted with ethyl acetate (300 ml×3). The organic layer was washed with water, saturated sodium bicarbonate solution and brine. The organic layer was then distilled off to yield product ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate. Yield: (16 g, 80%). ¹H NMR (CDCl₃): δ 7.20 (m 2H), 6.80 (d, J=7.9 Hz, 1H), 4.90 (bs, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H). Mass: (315, M+1,100%).

Step-2 2-(3-Bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid

Ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (16 g) was taken in acetic acid (100 ml) and to it added drop wise 70% nitric acid (10 ml) below 15° C. The reaction mixture was stirred for 2 h. After completion of the reaction; it was poured into 300 ml of ice water and extracted with ethyl acetate (300 ml×3). The ethyl acetate layer was washed with bicarbonate solution, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 12 g of 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid. The acid was taken in 50 ml of absolute ethanol and 2 ml of concentrated sulfuric acid and refluxed for 1 h. The ethanol layer was distilled off, washed it with water and dried gave 13 g of ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate intermediate. ¹H NMR (CDCl₃): δ 8.20 (s 1H), 7.20 (s, 1H), 4.90 (bs, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H). Mass: (360, M+1, 100%).

Step 3 Ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate

A solution of ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (4.1 g, 11.26 mmol) was taken in 50 ml of DMSO and to it added Cs₂CO₃ (3.02 g, 12.39 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then added cyclopropylmethyl bromide (1.67 g, 12.39 mmol) dropwise. After completion of addition, the reaction mixture was stirred at 70° C. for 4 h. After completion of the reaction, it was poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:3) as eluent provided 3 g of ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate. ¹H NMR (CDCl₃): δ 8.20 (s 1H), 7.20 (s, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (414, M+1, 100%).

Step 4 Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

To a solution of ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate (2 g, 4.83 mmol) in 30 ml of DMF/Water (25:5 ml) was added Pd(PPh₃)₄ (558 mg, 0.483 mmol), Cs₂CO₃ (5.5 g, 16.9 mmol) and 4-CF3-PhB(OH)₂ (1.01 g, 5.31 mmol) and the reaction mixture was stirred at 90° C. for 12 h. After completion of the reaction, it was poured into water (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 1.3 g of ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. ¹H NMR (CDCl₃): δ 8.20 (s 1H), 7.40-7.20 (m, 5H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (480, M+1, 100%).

Step 5 2-(6-(Cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (100 mg, 0.208 mmol) was taken in a mixture of MeOH; THF:Water (30 ml, 10:10:2) and to it added LiOH (30 mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was poured into water (50 ml) and extracted with ethyl acetate (100 ml x2). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:1) as eluent provided 70 mg of 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid. ¹H NMR (CDCl₃): δ 8.20 (s 1H), 7.40-7.20 (m, 5H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (452, M+1, 100%).

Example 554 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (300 mg, 0.626 mmo) was taken in 30 ml of Toluene:Water (1:1) and to it added Fe powder (203 mg, 3.62 mmol), Ammonium formate (228 mg, 3.62 mmol). The reaction mixture was refluxed for 3 h and then filtered through celite. The toluene was distilled off under reduced pressure and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 220 mg of ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. ¹H NMR (CDCl₃): δ 7.40-7.20 (m, 5H), 6.90 (s 1H), 4.50 (bs, 2H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (450, M+1, 100%).

Step 3 2-(5-Amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. (120 mg, 0.267 mmol) was taken in a mixture of MeOH; THF:Water (30 ml, 10:10:2) and to it added LiOH (30 mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was poured into water (50 ml) and extracted with ethyl acetate (100 ml x2). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:1) as eluent provided 80 mg of 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid. ¹H NMR (CDCl₃): δ 7.40-7.20 (m, 5H), 7.00 (s, 1H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (422, M+1, 100%).

Example 484 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

2-(6-Cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (150 mg, 0.33 mmol) was taken up in 10 ml of 6N HCl and a solution of sodium nitrite (30 mg, 0.40 mmol, 5 ml in water) was added at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then poured into a saturated solution of copper (II) chloride in water (25 ml) The reaction mixture was then heated at 70° C. for 3 hours. The mixture was cooled to room temperature and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography using ethyl acetate:hexane (2:3) as eluent to yield 120 mg of ethyl 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. ¹H NMR (CDCl₃): δ 7.60-7.45 (m, 5H), 7.20 (s 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (470, M+1, 100%).

Step 2 2-(6-Cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

The ethyl 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate above (120 mg, 0.207 mmol) was taken up in a mixture of MeOH; THF:Water (30 ml, 10:10:2) and LiOH (42 mg, 0.7 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were washed with 1N HCl, water and finally brine solution. The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography using ethyl acetate:hexane (1:1) as eluent to yield 105 mg of 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid product. ¹H NMR (CDCl₃): δ 7.65-7.40 (m, 5H), 7.20 (s, 1H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (442, M+1, 100%). HPLC Purity (99%).

Example 264 2-(6-cyclopropylmethoxy)-5-fluoro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (200 mg, 0.53 mmol) was taken up in 5 ml of 1,2-dichlorobenzene and a solution of BF3-etherate (1.5M, 5 ml) was added at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and t-butyl nitrite (1.5M, 3 ml) was added in a dropwise manner. The reaction mixture was then heated at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography using ethyl acetate:hexane (2:3) as eluent to provide 120 mg of ethyl 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. ¹H NMR (CDCl₃): δ 7.60-7.35 (m, 5H), 7.20 (s 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (453, M+1, 100%).

Step 2 2-(6-cyclopropylmethoxy)-5-fluoro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

The above ethyl 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (120 mg, 0.267 mmol) was taken up in MeOH; THF:Water (20 ml, 10:10:2) and LiOH (42 mg, 0.7 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. After completion, the reaction was poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate layers were washed with 1N HCl, water and finally brine solution. The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography using ethyl acetate:hexane (1:1) as eluent to yield 85 mg of 2-(6-cyclopropylmethoxy)-5-fluoro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid product. ¹H NMR (CDCl₃): δ 7.55-7.30 (m, 5H), 7.10 (s, 1H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (425, M+1, 100%). HPLC Purity (97%).

Example 724 2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid

Step 1 Diethyl 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonate

2-Isobutylmalonic acid diethyl ester (40.0 g, 0.185 mol) in DMF (50 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 8.0 g, 0.33 mol) in 200 mL DMF (200 mL) over 20 min. at 0° C. under nitrogen. The mixture was stirred for 0.5 h at room temperature, cooled to 0° C. and 1,2,4-trifluoro-5-nitro-benzene (30.0 g, 169.5 mmol) in DMF (150 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 h, poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO₄). Evaporation of solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc, gradient) to give 57.0 g (90%) of 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester as yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.87 (dd, J=12.3, 6.0 Hz, 1H), 7.79 (dd, J=10.1, 6.4 Hz, 1H), 4.30-4.18 (m, 4H), 2.27 (d, J=5.8 Hz, 2H), 1.60-1.50 (m, 1H), 1.26 (t, J=7.1 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 168.2, 155.1 (d, ¹J_(CF)=252.3 Hz), 150.9 (d, ¹J_(CF)=263.2 Hz), 135.7, 135.1, 120.0 (dd, ²J_(CF)=26.0, ³J_(CF)=4.0 Hz), 113.0 (d, ²J_(CF)=29.0 Hz), 62.3, 43.1, 24.9, 23.8, 13.8.

Step 2 2-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid

The above 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester (57.0 g, 152.8 mmol) was dissolved in AcOH/H₂O/EtOH (400 mL/120 mL/50 mL) and the reaction mixture was heated under reflux for 96 h. After cooling the solvent was evaporated under reduced pressure and water (200 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL), and the combined extracts were washed with water (3×100 mL), brine (100 mL) and dried (MgSO₄). Evaporation of solvent under reduced pressure gave a yellow oil which crystallized on standing to yield 27 g of 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid. Chromatography of the residual oil (Heptane-EtOAc gradient) gave an additional 3 g of product (72% combined yield). ¹H NMR (300 MHz, CDCl₃/TMS): δ 9.63 (br s, 1H), 7.82 (dd, J=8.8, 6.0 Hz, 1H), 7.38 (dd, J=11.0, 5.8 Hz, 1H), 4.14-4.08 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 177.6, 158.2 (d, ¹J_(CF)=232.5 Hz), 150.9 (d, ¹J_(CF)=262.5 Hz), 136.0, 134.7, 119.0 (d, ²J_(CF)=20.0, Hz), 113.1 (d, ²J_(CF)=29.4 Hz), 41.7, 41.3, 26.0, 22.6, 21.9.

Step 3 2-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester

2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.11 mol) was dissolved in EtOH (200 mL) and H₂SO₄ (96%) 10 mL added. The reaction mixture was refluxed for 3 h and the solvent evaporated to an oil which was dissolved in EtOAc. Water (150 mL) added and the reaction mixture was extracted with EtOAc (3×100 mL). Organic phases washed with saturated NaHCO₃ (50 mL), water (100 mL) and brine (100 mL) then dried under MgSO₄. The evaporation of solvent under reduced pressure gave 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester as yellow oil 32.0 g, (97%), which was used for the next step without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.81 (dd, J=8.8, 6.2 Hz, 1H), 7.41 (dd, J=11.1, 5.6 Hz, 1H), 4.23-4.05 (m, 3H), 2.04-1.94 (m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.95-0.92 (m, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 171.6, 155.0 (d, ¹J_(CF)=246.0 Hz), 151.5 (d, ¹J_(CF)=261.3 Hz), 145.5, 135.7, 118.8 (dd, ²J_(CF)=24.0, ³J_(CF)=4.0 Hz), 113.0 (d, ²J_(CF)=20.0 Hz), 61.6, 41.8, 26.1, 22.5, 22.0, 14.1.

Step 4 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

Cyclopropylmethanol (10.0 g, 138.8 mmol) was treated with n-BuLi (2.5M in hexane 7.4 g, 46 mL, 115.6 mmol) at −15° C. under nitrogen, and the reaction mixture was stirred 1 h at 25° C. To the mixture was added 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester (29 g, 96 mmol) in Cyclopropylmethanol (30 mL) dropwise at 25° C. and the reaction mixture stirred for an additional 16 h. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases washed with water (3×100 mL), brine (100 mL) and dried (MgSO₄). Evaporation of the solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 29.5 g, (81%) of 2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.60 (d, J=9.0 Hz, 1H), 7.15 (d, J=5.7 Hz, 1H), 4.07 (t, J=7.7 Hz, 1H), 4.00-3.80 (m, 4H), 2.01-1.92 (m, 1H), 1.68-1.60 (m, 1H), 1.52-1.43 (m, 1H), 1.34-1.20 (m, 1H), 1.19-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.65 (d, J=7.7 Hz, 2H), 0.54 (d, J=7.7 Hz, 2H), 0.39 (d, J=4.4 Hz, 2H), 0.25 (d, J=4.4 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 172.6, 152.7 (d, ¹J_(CF)=243.4 Hz), 148.8, 138.1, 133.3 (d, ²J_(CF)=15.7 Hz), 115.8, 112.6 (d, ²J_(CF)=29.5 Hz), 75.1, 70.0, 42.1, 41.7, 26.1, 22.5, 22.2, 10.0, 9.8, 3.4.

Step 5 2-(5-Cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (10.0 g, 26.4 mmol) was dissolved in EtOH (200 mL) and hydrogenated at 50 psi, 25° C. for 24 h over 10% Pd—C (1 g). The mixture was filtered and the solvent evaporated to give crude a brown oil, which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 6.7 g, (72%) of 2-(5-cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.73 (d, J=6.9 Hz, 1H), 6.40 (d, J=11.0 Hz, 1H), 4.00-3.70 (m, 5H), 1.91-1.81 (m, 1H), 1.65-1.56 (m, 1H), 1.51-1.39 (m, 1H), 1.28-1.18 (m, 1H), 1.12-1.00 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.63-0.57 (m, 2H), 0.53-047 (m, 2H), 0.35-0.28 (m, 2H), 0.25-0.18 (m, 2H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 174.2, 154.8 (d, ¹J_(CF)=236.0 Hz), 142.6, 136.6 (d, ³J_(CF)=11.5 Hz), 114.1 (d, ²J_(CF)=16.8 Hz), 111.6 (d, ³J_(CF)=4.8 Hz), 101.6 (d, ²J_(CF)=28.2 Hz), 73.8, 69.2, 42.1, 40.8, 25.9, 22.7, 22.2, 10.5, 9.8, 3.2.

Step 6 2-(5-Cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(5-cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (2.9 g, 8.3 mmol) was dissolved in a mixture of EtOH/H₂O/H₂SO₄ (96%) 50 mL/100 mL/2.5 mL at 0° C. A solution of NaNO₂ (0.63 g, 9.1 mmol) in water (20 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 20 min. A solution of KI (4.0 g, 24.1 mmol) in water (20 mL) was added dropwise at 0° C. and the reaction mixture was heated 50-60° C. for 2.5 h. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with 10% sodium thiosulfate (30 mL) followed by brine (30 mL) and then dried over MgSO₄. and solvent evaporated to give crude brown oil, which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 2.2 g, (57%) of 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.46 (d, J=8.8 Hz, 1H), 6.83 (d, J=6.3 Hz, 1H), 4.01-3.83 (m, 5H), 1.96-1.86 (m, 1H), 1.69-1.58 (m, 1H), 1.51-1.39 (m, 1H), 1.28-1.18 (m, 1H), 1.12-1.00 (m, 1H), 0.91 (d, J=6.3 Hz, 6H), 0.66-0.60 (m, 2H), 0.55-047 (m, 2H), 0.42-0.34 (m, 2H), 0.26-0.18 (m, 2H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.2, 154.3 (d, ¹J_(CF)=243.4 Hz), 154.1, 127.1 (d, ²J_(CF)=16.2 Hz), 125.5 (d, ²J_(CF)=26.4 Hz), 112.3 (d, ³J_(CF)=3.6 Hz), 84.6 (d, ³J_(CF)=8.4 Hz), 74.5, 69.6, 41.9, 41.5, 26.0, 22.7, 22.2, 10.2, 9.8, 3.3.

Step 7 2-(2-Cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.2 g, 0.43 mmol) in anhydrous DME (10 mL) under argon was added 4-trifluoromethylphenylboronic acid (0.1 g, 0.53 mmol), CsF (0.16 g, 1.05 mmol), and Pd(PPh₃)₄ (0.015 g, 0.013 mmol). The reaction mixture was refluxed for 18 h, a water/EtOAc 15/15 mL mixture was added and the organic phase was separated and dried over MgSO₄. The solvent was then evaporated to give a yellow oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 0.18 of 2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a light yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.70-7.64 (m, 4H), 7.05 (d, J=10.4 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.09 (t, J=7.7 Hz, 1H), 4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05 (m, 2H), 0.95 (d, J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.5, 154.3 (d, ¹J_(CF)=239.7 Hz), 151.9, 140.7, 132.0, 129.5, 126.6 (d, ²J_(CF)=16.9 Hz), 124.8 (q, ³J_(CF)=3.7 Hz), 124.0 (q, ¹J_(CF)=271.6 Hz), 117.0 (d, ²J_(CF)=24.6 Hz), 113.6, 74.1, 69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8, 3.2.

Step 8 2-(2-Cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid

2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.14 g, 0.29 mmol) was dissolved in a mixture of EtOH/H₂O (9 ml/1 ml) and KOH 0.3 g added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO₄ and evaporated under reduced pressure to an oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 0.12 g of a white solid. A second chromatography of the solid gave 0.03 g (25%) of pure 2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid product as a crystalline white solid. M.P.=110-111° C., ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.99 (br s 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.32-1.05 (m, 2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H), 0.24 (d, J=3.9 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.2, 154.7 (d, ¹J_(CF)=239.8 Hz), 152.0, 140.6, 132.0, 129.9, 129.6, 125.7 (d, ²J_(CF)=16.2 Hz), 124.8 (q, ³J_(CF)=3.6 Hz), 124.0 (q, ¹J_(CF)=270 Hz), 117.2 (d, ²J_(CF)=25.2 Hz), 113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1, 10.3, 3.2.

Example 485 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1 Ethyl 2-(3-bromo-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.11 mol) in 200 ml of CCl₄, was slowly added bromine (18.8 g, 0.11 mol) dissolved in 10 ml of CCl₄ at 0° C. for 30 min. The reaction mass was stirred for another 30 min at 0° C. After completion of the reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with water, and 10% sodium bi-sulfite solution, dried over Na₂SO₄, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-4-hydroxyphenyl)acetate in 78% yield. (22.4 g). ¹HNMR (CDCl₃): 7.42 (s, 1H); 7.14 (d, 1H); 6.97 (d, 1H); 5.53 (bs, 1H); 4.13 (q, 2H); 3.52 (s, 2H); 1.16 (t, 3H).

Step 2 Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(3-bromo-4-hydroxyphenyl)acetate (20 g, 0.076 molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol) and the mixture was refluxed. Sulfuryl chloride (6.8 ml 0.846 mol) was slowly added under over a period of 10 min. The reaction mixture was refluxed for a further 5 h. Upon completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layer were washed with 10% NaHCO₃ solution and water, dried over Na₂SO₄, filtered and evaporated under vacuum to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g). ¹H NMR (CDCl₃): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs, 1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).

Step 3 Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (4 g, 0.011 mol) and K₂CO₃ (2.8 g, 0.02 mol) in 100 ml of DMSO was slowly added cyclopropyl methylbromide (1.46 ml, 0.017 mol) at room temperature. Upon completion of the addition, the reaction mixture was heated at 60° C. for 4 h. Upon completion of the reaction, the mixture was poured onto water and extracted with EtOAc (×2). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate in 72% yield. (93.4 g). ¹HNMR (CDCl₃): 7.38 (bs, 1H); 7.28 (s, 1H); 4.16 (q, 2H); 3.87 (d, 2H); 3.58 (s, 2H); 1.38 (m, 1H); 1.28 (t, 3H); 0.63 (m, 2H); 0.38 (m, 2H).

Step 4 Ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate

A mixture of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (4 g, 0.011 mol), 4-Trifluoromethyl phenylboronic acid (2.6 g, 0.012 mol), Palladium Tetrakis (triphenylphosphine)(1.3 g, 0.001 mol), Cesium carbonate (13.1 g, 0.04 mol) in DMF/water mixture (100 ml/5 ml) was stirred overnight at 100° C. Upon completion of reaction, the precipitate were removed by filtration. The filtrate was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by Flash Column Charomatography to give ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate in 57% yield. (2.7 g). ¹HNMR (CDCl₃): 7.69 (bs, 4H); 7.36 (s, 1H); 7.17 (s, 1H); 4.18 (q, 2H); 3.59 (s, 2H); 3.39 (d, 2H); 1.28 (t, 3H); 0.96 (m, 1H); 0.41 (m, 2H); 0.01 (m, 2H).

Step 5 Ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

To a suspension of NaH (37 mg, 50% suspension, 0.79 mmol) in 25 ml of DMF was slowly added a mixture of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (300 mg, 0.719 mmol) and cyclopropylmethyl bromide (108 mg, 0.782 mmol) in 20 ml of DMF at 0° C. for 15 min under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred for 15 min at 0° C. The reaction mixture was poured onto crushed ice and extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by Flash column Chromatography to give ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate in 62% yield. (0.210 g). ¹HNMR (CDCl₃): 7.69 (s, 4H); 7.41 (s, 1H); 7.21 (s, 1H); 4.19 (q, 2H); 3.63 (t, 1H); 3.41 (d, 2H); 1.94 (m, 1H); 1.78 (m, 1H); 1.27 (t, 3H); 0.97 (bs, 1H); 0.72 (bs, 1H); 0.42 (m, 4H); 0.13 (m, 2H); 0.1 (m, 2H).

Step 6 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

A mixture of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (100 mg, 0.214 mmol) and lithium hydroxide monohydrate (27 mg, 0.642 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. Upon completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with EtOAc (×2). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid in 56% yield. (52.6 mg). ¹HNMR (CDCl₃): 7.71 (s, 4H); 7.42 (s, 1H); 7.23 (s, 1H); 3.68 (t, 1H); 3.41 (d, 2H); 1.93 (m, 1H); 1.77 (m, 1H); 0.97 (bs, 1H); 0.71 (bs, 1H); 0.42 (m, 4H); 0.12 (m, 2H); 0.1 (m, 2H).

Example 414 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate

To a stirred solution compound ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (6 g), in dry methanol (100 mL) was added Pd(OH)₂ under an atmosphere of nitrogen. The reaction mixture was stirred for 5 h under an atmosphere of hydrogen. The reaction mixture was filtered through Celite™, washed with methanol and concentrated to dryness under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate (4 g, 72%). ¹HNMR (CDCl₃, 200 MHz): 6.80 (s, 1H); 6.62 (s, 1H); 5.35 (bs, 1H); 4.13 (q, 2H); 3.41 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H).

Step 2 Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate

Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate 1 (4 g, 0.012 mol) was dissolved in a mixture of ACN/H₂O/HCl 60 mL/30 mL/8 mL at 0° C. A solution of NaNO₂ (0.919 g, 1.1 eq) in water (10 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 1 h at 0° C. A solution of CuCl (5.99 g, 0.060 mol) in water (10 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was then heated to 50° C. for 2.5 h. upon which the mixture was poured into ice water, extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over NaSO₄ and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate as yellow oil 2.2 g, (47.3%). ¹HNMR (CDCl₃, 200 MHz): 7.38 (s, 1H); 7.4 (s, 1H); 5.80 (bs, 1H); 4.13 (q, 2H); 3.51 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H);

Step 3 Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methyl pentanoate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate (2 g, 0.57 mmol) and K₂CO₃ (1.58 g, 0.011 mol) in dry DMF (20 mL), slowly added trifluoroethyl iodide (7.2 g, 3.39 ml, 0.034 mol) at room temperature. Upon completion of the addition, the reaction mixture was slowly heated to 100° C. for 4 h. Upon completion, the reaction mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic layer were washed with water, dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.4 g, 60% yield). ¹HNMR (CDCl₃, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);

Step 4 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

A mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1 g, 1 eq), 4-Trifluoromethyl phenylboronic acid (2.6 g, 1.4 eq), Pd(PPh₃)₄ (1.3 g, 0.1 eq) and Cesium Fluoride (13.1 g, 2 eq) in DME (30 ml) was stirred for overnight at 100° C. Upon completion, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water followed by brine, dried over Na₂SO₄ and concentrated under vacuo. The residue was purified by Flash Column Chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate in 74% yield (1.08 g). ¹HNMR (CDCl₃, 400 MHz): 7.68 (m, 5H), 7.43 (s, 1H); 7.24 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);

Step 5 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (800 mg, mmol) and lithium hydroxide monohydrate (27 mg, 0.642 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid in 88% yield (670 mg).

Or alternatively example 414 may be synthesized via the following procedures:

Step 1 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.75 g, 1.70 mmol) was dissolved in anhydrous DMF (20 mL), NaH (60% wt. in paraffin oil, 0.049 g, 2.04 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature, upon which isobutyl bromide (0.2 mL, 1.87 mmol), was added in a drop wise manner at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and then saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with water (2×10 mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a colorless oil, witch was purified by flash column chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.5 g, 59% yield) as a thick liquid.

Step 2 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methyl pentanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.6 g, 1.21 mmol) and lithium hydroxide monohydrate (0.509 g, 12.1 mmol) in MeOH/THF/Water a solvent mixture (10 mL/10 mL/10 mL) was stirred for 4 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×20 mL). The combined organic layers washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methyl pentanoic acid (0.4 g, 72% yield) as a white solid.

Example 1055 2-(6-Cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic Acid Step 1 Diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate

To a solution of diethyl isobutylmalonate (50.0 g, 231 mmol) in anhydrous DMF (200 mL) cooled in an ice bath was added NaH (60%, 11.1 g, 277 mmol) in small portions. After the addition, the reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. 5-Chloro-2-nitrobenzotrifluoride (47.3 g, 210 mmol) in anhydrous DMF (50 mL) was added dropwise and the mixture was stirred at room temperature for two days. The DMF was removed under high vacuum and the residue was diluted with ethyl acetate (400 mL). Water (400 mL) was added dropwise; ammonium chloride (25 g) was added and the layers were separated. The organic layer was washed with brine (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a red-brown oil, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (12:1) to give the desired product diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 87%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃): δ 8.07 (s, 1H), 7.94 (d, 2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz), 4.25 (m, 4H), 2.33 (d, 2H, J=6.6 Hz), 1.51 (m, 1H), 1.26 (t, 6H, J=7.2 Hz), 0.84 (d, 6H, J=6.6 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 169.23, 146.71, 142.86, 132.94, 127.94 (q, J=5 Hz), 124.55, 123.12 (q, J=33 Hz), 121.79 (q, J=272 Hz), 62.19, 61.59, 44.16, 24.66, 23.66, 13.89.

Step 2 4-Methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid

To a solution of diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 184 mmol) in acetic acid (500 mL) were added water (157 mL) and concentrated H₂SO₄ (55 mL) carefully. The reaction mixture was refluxed for three days and then concentrated under reduced pressure. The residue was diluted with water (400 mL) and extracted with ethyl acetate (6×100 mL). The combined organic extracts were washed with water (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a brown oil. The residue was purified by silica-gel flash chromatography eluting with heptane/EtOAc (5:1 and then 2:1) to give 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.5 g, 76%) as a yellowish oil: ¹H NMR (300 MHz, CDCl₃): δ 11.51 (s, 1H, br), 7.87 (d, 1H, J=8.4 Hz), 7.78 (s, 1H), 7.71 (d, 1H, J=8.4 Hz), 3.84 (t, 1H, J=7.8 Hz), 2.06 (m, 1H), 1.72 (m, 1H), 1.49 (m, 1H), 0.95 (d, 3H, J=6.6. Hz), 0.94 (d, 3H, J=6.3 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 178.76, 147.09, 143.94, 132.66, 127.70 (q, J=5 Hz), 125.40, 123.95 (q, J=34 Hz), 121.74 (q, J=271 Hz), 42.16, 25.96, 22.44, 22.09.

Step 3 4-Methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester

To a solution of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.3 g, 139 mmol) in absolute ethanol (300 mL) was added concentrated sulfuric acid (95-98%, 9.0 mL) and the solution was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure; the residue was treated with a solution of sodium carbonate (5%, 300 mL) and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification by silica-gel flash chromatography eluting with heptane/EtOAc (10:1) gave 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester (38.4 g, 83%) as a yellowish oil: ¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, 1H, J=8.4 Hz), 7.82 (s, 1H), 7.74 (dd, 1H, J=8.4, 1.5 Hz), 4.18 (m, 2H), 3.83 (t, 1H, J=7.5 Hz), 2.06 (m, 1H), 1.70 (m, 1H), 1.50 (m, 1H), 1.27 (t, 3 H, J=7.2 Hz), 0.97 (d, 3H, J=6.6 Hz), 0.96 (d, 3H, J=6.3 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 172.24, 146.83, 145.04, 132.40, 127.51 (q, J=5 Hz), 125.28, 123.80 (q, J=32 Hz), 121.78 (q, J=272 Hz), 61.45, 49.45, 42.65, 26.03, 22.41, 22.17, 14.10.

Step 4 2-(4-Amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

A suspension of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester (38.3 g, 115 mmol), tin (II) chloride (87.2 g, 460 mmol) and water (16.6 g, 920 mmol) in ethanol (500 mL) was heated at reflux for four hours. The reaction mixture was concentrated under reduced pressure; the residue was treated with ethyl acetate (300 mL) and aqueous NaOH solution (1 N, 2.5 L). The aqueous layer was extracted with ethyl acetate (3×600 mL). The combined organic layers were washed with brine (1 L), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (10:1) to give 2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (31.1 g, 89%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃): δ 7.35 (d, 1H, J=2.1 Hz), 7.27 (dd, 1H, J=8.4, 2.1 Hz), 6.69 (d, 1H, J=8.4 Hz), 4.10 (m, 4H), 3.54 (t, 1H, J=7.8 Hz), 1.91 (m, 1 H), 1.58 (m, 1H), 1.44 (m, 1H), 1.21 (t, 3H, J=6.9 Hz), 0.90 (d, 3H, J=6.6 Hz), 0.89 (d, 3H, J=6.6 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 174.14, 143.45, 132.22, 128.58, 125.91 (q, J=4 Hz), 124.80 (q, J=271 Hz), 117.35, 113.60 (q, J=29 Hz), 60.60, 48.54, 42.35, 25.77, 22.46, 22.18, 14.04.

Step 5 2-(4-Hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

To sulfuric acid (95-98%, 20.0 mL) was added 2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (6.06 g, 20.0 mmol). The mixture was cooled to 0° C. and water (30.0 mL) was added dropwise. A solution of NaNO₂ (1.66 g, 24.0 mmol) in water (12 mL) was added dropwise and the mixture was stirred for additional 20 min. A few crystals of urea were added to decompose any excess NaNO₂. A solution of cupric nitrate (466 g, 2.00 mol) in water (880 mL) was added, followed by addition of Cu₂O (2.86 g, 20.0 mmol). The mixture was stirred for 5 min and diethyl ether (1 L) was added. The organic extract was washed with brine (500 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (20:1) to give 2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (2.20 g, 31%) as a yellow oil: HRMS (DIP-CI-MS): calcd for C₁₅H₁₉NO₅F₃ (M+H)⁺: 350.1215. found 350.1240; ¹H NMR (300 MHz, CDCl₃): δ 11.13 (s, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 4.15 (m, 2H), 3.69 (t, 1H, J=7.8 Hz), 2.00 (m, 1H), 1.62 (m, 1H), 1.47 (m, 1H), 1.25 (t, 3 H, J=7.2 Hz), 0.94 (d, 3H, J=6.3 Hz), 0.93 (d, 3H, J=6.6 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 172.75, 152.45, 134.67 (q, J=5 Hz), 134.29, 131.40, 127.90, 122.35, (q, J=271 Hz), 121.42 (q, J=32 Hz), 61.51, 48.76, 42.76, 26.23, 22.60, 22.42, 14.32.

Step 6 2-(4-Cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

To a solution of 2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (2.66 g, 7.62 mmol), cyclopropanemethanol (0.60 g, 8.38 mmol) and triphenylphosphine (2.40 g, 9.14 mmol) in anhydrous THF (32 mL) was added diethyl azodicarboxylate (40 wt % solution in toluene, 3.98 g, 9.14 mmol) dropwise. The reaction mixture was stirred at room temperature for two days and then concentrated under reduced pressure. The residue was triturated with THF/hexane (1:5, 3×15 mL). The combined extracts were concentrated under reduced pressure to give a yellow solid, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (60:1 and then 10:1) to give 2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (1.89 g, 61%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃): δ 7.92 (s, 1H), 7.73 (s, 1H), 4.06 (m, 2H), 3.79 (d, 2 H, J=7.2 Hz), 3.64 (t, 1H, J=7.5 Hz), 1.93 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.24 (m, 1H), 1.17 (t, 3H, J=6.9 Hz), 0.86 (m, 6H), 0.56 (d, 2H, J=6.6 Hz), 0.27 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 172.49, 149.98, 144.40, 135.55, 130.96 (q, J=5 Hz), 128.29, 126.77, (q, J=31 Hz), 122.37 (q, J=272 Hz), 82.03, 61.37, 48.74, 42.66, 26.04, 22.36, 22.32, 14.14, 10.66, 3.39.

Step 7 2-(3-Amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

A mixture of 2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (1.85 g, 4.59 mmol) and Pd/C (1.85 g) in ethanol and 1 N HCl (4.60 mL) was hydrogenated under 36 psi H₂ in a Parr apparatus. After 4 h, the reaction mixture was filtered through Celite 521®. The filtrate was concentrated under reduced pressure to give a yellow oil. The residue was treated with an aqueous solution of sodium carbonate (3 g in 100 mL of water) and the resulting solution was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a brown oil, which was purified by silica-gel flash chromatography eluting with a gradient of heptane/ethyl acetate (from 10:1 to 2:1) to give 2-(3-amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (0.88 g, 51%) as a light pink oil: ¹H NMR (300 MHz, CDCl₃): δ 6.83 (s, 1 H), 6.80 (s, 1H), 4.04 (m, 2H), 3.85 (s, 2H), 3.66 (d, 2H, J=6.9 Hz), 3.45 (t, 1H, J=7.8 Hz), 1.84 (m, 1H), 1.49 (m, 1H), 1.39 (m, 1H), 1.22 (m, 1H), 1.14 (t, 3H, J=7.2 Hz), 0.82 (m, 6H), 0.56 (d, 2H, J=7.5 Hz), 0.27 (d, 2H, J=4.5 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 173.61, 142.71, 141.25, 135.51, 123.75 (q, J=30 Hz), 123.52 (q, J=271 Hz), 118.46, 115.52 (q, J=5 Hz), 77.88, 60.70, 49.03, 42.53, 25.86, 22.40, 22.31, 14.07, 10.98, 3.19.

Step 8 2-(4-Cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

To a solution of p-toluenesulfonic acid monohydrate (0.308 g, 1.62 mmol) in acetonitrile (2.3 mL) was added 2-(3-amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (0.20 g, 0.54 mmol). The resulting suspension of the amine salt was cooled in an ice bath. A solution of sodium nitrite (0.0745 g, 1.08 mmol) in water (0.32 mL) was added dropwise, followed by addition of a solution of KI (1.79 g, 10.8 mmol) in water (2.0 mL). The reaction mixture was stirred in the ice bath for one hour and then at room temperature for one hour. TLC showed that the reaction was completed. Water (20 mL) was added and then an aqueous solution of sodium bicarbonate (1 M) to adjust the pH to 8. Ethyl acetate (20 mL) was added for extraction. The organic layer was washed with aqueous Na₂S₂O₄ solution (10%, 20 mL) and brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give a brown oil, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (30:1) to give 2-(4-cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (0.15 g, 57%) as a yellowish oil: ¹H NMR (300 MHz, CDCl₃): δ 7.93 (s, 1H), 7.52 (s, 1H), 4.11 (m, 2H), 3.83 (d, 2H, J=7.2 Hz), 3.59 (t, 1 H, J=7.5 Hz), 1.95 (m, 1H), 1.50 (m, 3H), 1.22 (t, 3H, J=6.9 Hz), 0.91 (d, 3H, J=6.3 Hz), 0.90 (d, 3H, J=6.3 Hz), 0.64 (m, 2H), 0.43 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 172.96, 155.55, 142.66, 136.98, 126.94 (q, J=5 Hz), 124.87 (q, J=30 Hz), 122.64 (q, J=272 Hz), 93.73, 79.79, 61.06, 48.53, 42.65, 26.01, 22.39, 14.16, 10.75, 3.36.

Step 9 2-(6-Cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid ethyl ester

A mixture of 2-(4-cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (0.14 g, 0.29 mmol), 4-(trifluoromethyl)benzeneboronic acid (0.089 g, 0.47 mmol), Pd(dppf)Cl₂ (0.023 g, 0.031 mmol) and a solution of aqueous sodium carbonate (2 M, 0.31 mL, 0.62 mmol) in 1,4-dioxane (4 mL) was degassed and heated at 100° C. for ten days. The reaction mixture was concentrated under reduced pressure; the residue was treated with water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with heptane/ethyl acetate (100:1) to give a colorless oil (0.11 g), which was further purified by flash chromatography on silica gel 100 C_(B)-reversed phase eluting with MeOH/H₂O (5:1 to 20:3) to give 2-(6-cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid ethyl ester (0.05 g, 34%) as a white solid: ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.73 (m, 4H), 7.58 (s, 1H), 7.48 (s, 1 H), 4.13 (m, 2H), 3.70 (t, 1H, J=7.5 Hz), 3.27 (d, 2H, J=7.2 Hz), 2.00 (m, 1H), 1.67 (m, 2H), 1.51 (m, 1H), 1.25 (t, 3H, J=7.2 Hz), 0.93 (m, 8H), 0.45 (d, 2H, J=7.5 Hz); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.35, 153.80, 140.99, 135.48, 135.40, 134.05, 130.05 (q, J=32 Hz), 129.88 (q, J=32 Hz), 129.42, 126.41 (q, J=5 Hz), 125.33 (q, J=4 Hz), 124.06 (q, J=270 Hz), 123.48 (q, J=270 Hz), 79.47, 60.98, 49.21, 42.87, 26.19, 22.46, 14.22, 10.56, 3.13.

Step 10 2-(6-Cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid

A mixture of 2-(6-cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid ethyl ester (0.04 g, 0.08 mmol) and aqueous KOH (1.4 M, 0.4 mL) in ethanol (5 mL) was stirred at room temperature for two days. After the solvent was removed under reduced pressure, the residue was diluted with water (30 mL), acidified with 1 N HCl to pH 1, and then extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and freeze-dried overnight to give the desired carboxylic acid 2-(6-cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid (0.04 g, 100%) as a white solid: mp 148-149° C.; HRMS (ESI-TOF): calcd for C₂₄H₂₃O₃F₆Na₂ (M−H+2 Na)⁺: 519.1341. found 519.1366; ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.72 (m, 4H), 7.59 (s, 1H), 7.48 (s, 1H), 3.73 (m, 1H), 3.27 (d, 2H, J=6.9 Hz), 2.02 (m, 1H), 1.69 (m, 1H), 1.56 (m, 1 H), 1.28 (m, 1H), 0.94 (m, 8H), 0.46 (m, 2H); the proton of COOH was not observed; ¹³C NMR (75 MHz, CDCl₃/TMS): δ 178.95, 154.12, 140.82, 135.61, 134.49, 134.24, 130.18 (q, J=32 Hz), 129.44 (q, J=32 Hz), 129.40, 126.50 (q, J=5 Hz), 125.39 (q, J=4 Hz), 124.04 (q, J=270 Hz), 123.40 (q, J=271 Hz), 79.55, 48.91, 42.35, 26.07, 22.49, 22.35, 10.58, 3.15; HPLC purity: 95.2%, retention time=11.78 min.

Example 754 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoic acid

Step 1 Cyclopropylmethyl 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate

To a solution of 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.2 g, 0.43 mmol) in DME (anhydrous, 10 mL) under argon atmosphere was added 4-trifluoromethylphenylboronic acid (0.1 g, 0.53 mmol), CsF (0.16 g, 1.05 mmol), and Pd(PPh₃)₄ (0.015 g, 0.013 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO₄ and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatograph using Heptane-EtOAc (60:1-9:1) to give cyclopropylmethyl 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate as a yellowish oil (0.18 g, 90%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.70-7.64 (m, 4H), 7.05 (d, J=10.4 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.09 (t, J=7.7 Hz, 1H), 4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05 (m, 2H), 0.95 (d, J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.5, 154.3 (d, ¹J_(CF)=239.7 Hz), 151.9, 140.7, 132.0, 129.5, 126.6 (d, ²J_(CF)=16.9 Hz), 124.8 (q, ³J_(CF)=3.7 Hz), 124.0 (q, ¹J_(CF)=271.6 Hz), 117.0 (d, ²J_(CF)=24.6 Hz), 113.6, 74.1, 69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8, 3.2.

Step 2 2-(4-benzo[1,2,5]oxadiazol-5-yl-5-cyclopropylmethoxy-2-fluoro-phenyl)-4-methylpentanoic acid

Cyclopropylmethyl 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate (0.14 g, 0.29 mmol) was dissolved in a mixture of EtOH/H₂O (9 mL/1 mL) and KOH (0.3 g) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄ and evaporated under reduced pressure to give a colorless oil. Purification by gradient column chromatography on silica gel Heptane-EtOAc (50:1-9:1) gave 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoic acid as a white solid (0.12 g, quantitative); pure portion (0.03 g, 25%); white microcrystals, M.P.=110-111° C., ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.99 (br s, 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.32-1.05 (m, 2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H), 0.24 (d, J=3.9 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.2, 154.7 (d, ¹J_(CF)=239.8 Hz), 152.0, 140.6, 132.0, 129.9, 129.6, 125.7 (d, ²J_(CF)=16.2 Hz), 124.8 (q, ³J_(CF)=3.6 Hz), 124.0 (q, ¹J_(CF)=270 Hz), 117.2 (d, ²J_(CF)=25.2 Hz), 113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1, 10.3, 3.2.

Example 2959 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid

Step 1 2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl ester

To a solution of 2-isobutylmalonic acid diethyl ester (75.0 g, 0.35 mol) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 13.0 g, 0.57 mol) over 20 min. at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to 25° C. The reaction mixture was cooled down to 0° C. again and a solution of 2,4-difluoronitro-benzene (50.0 g, 0.31 mol) in DMF (150 mL) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. After cooling, the reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases washed with water (3×100 mL), brine (100 mL), and dried (MgSO₄). Evaporation of the solvent under reduced pressure gave a brown oil. The crude product (92.0 g, 82%) was used for the next step without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.03 (t, J=8.4 Hz, 1H), 7.70 (dd, J=12.9, 1.7 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.25-4.18 (m, 4H), 2.28 (d, J=6.3 Hz, 2H), 1.54-1.45 (m, 1H), 1.25 (t, J=7.0 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 169.2, 154.5 (d, ¹J_(CF)=263.1 Hz), 146.9 (d, unresolved), 125.3, 124.1 (d, ³J_(CF)=3.6 Hz), 118.6 (d, ²J_(CF)=23.3 Hz), 62.0, 60.3, 44.1, 24.7, 23.6, 13.9.

Step 2 2-(3-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid

2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl ester (92.0 g, 0.26 mol) was dissolved in AcOH/H₂O/H₂SO₄ (96%) (500 mL/200 mL/70 mL) and the reaction mixture was refluxed for 24 h. After cooling and evaporation, water (300 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO₄). The evaporation of solvent under reduced pressure gave a brown oil (61 g, quantitative), which was used for the next step without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.07-8.01 (m, 1H), 7.33-7.26 (m, 2H), 3.79-3.73 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 178.3, 156.0 (d, ¹J_(CF)=232.5 Hz), 147.0, 136.0, 126.2, 124.3, 118.1 (d, ²J_(CF)=30 Hz), 49.3, 42.0, 25.8, 22.4, 22.0.

Step 3 2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester

2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.12 mmol) was dissolved in EtOH (100 mL) and H₂SO₄ (96%, 5 mL) was added. The reaction mixture was refluxed for 3 h and the solvent evaporated. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with saturated NaHCO₃ solution (50 mL), water (100 mL) and brine (100 mL), and then dried over MgSO₄. Evaporation of the solvent under reduced pressure gave a brown oil (31.0 g, 97%), which was used for the next step without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.03 (t, J=8.4 Hz, 1H), 7.33-7.26 (m, 2H), 4.17-4.11 (m, 2H), 3.73 (t, J=7.6 Hz, 1H), 2.10-1.94 (m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.0 Hz, 3H), 0.95-0.92 (m, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 172.2, 155.3 (d, ¹J_(CF)=265.0 Hz), 148.3 (d, ³J_(CF)=8.4 Hz), 136.5, 126.1, 124.1 (d, ³J_(CF)=3.6 Hz), 117.8 (d, ²J_(CF)=21.6 Hz), 61.3, 49.4, 42.3, 25.9, 22.5, 22.1, 14.1.

Step 4 2-(3-Cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

Cyclopropylmethanol (80.0 g, 1.11 mol) was treated with n-BuLi (2.5 M in hexane, 9.1 g, 57 mL, 0.14 mol) at a temperature ranging from −15 to 0° C. The reaction mixture was stirred for 1 h at 25° C. Then, a solution of 2-(3-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester in cyclopropylmethanol (30 mL) was added at 25° C. and the reaction mixture was stirred for 16 h. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL), and dried (MgSO₄). Evaporation of the solvent under reduced pressure gave a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (9:1-4:1) to give 2-(3-cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (34.0 g, 93%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.78 (d, J=8.4 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 4.00-3.83 (m, 4H), 3.69 (t, J=8.0 Hz, 1H), 2.07-1.92 (m, 1H), 1.69-1.60 (m, 1H), 1.52-1.42 (m, 1H), 1.32-1.20 (m, 1H), 1.19-1.00 (m, 1H), 0.92 (d, J=6.3 Hz, 6H), 0.68-0.62 (m, 2H), 0.56-0.48 (m, 2H), 0.42-0.38 (m, 2H), 0.26-0.21 (m, 2H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 172.9, 152.3, 146.2, 138.8, 125.6, 119.8, 114.4, 74.2, 69.8, 49.8, 42.6, 26.0, 22.5, 22.2, 10.0, 9.7, 3.3.

Step 5 2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(3-Cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (34.0 g, 94.2 mmol) was dissolved in AcOH (300 mL) and water (20 mL). Then, Zn powder (60.0 g, 923 mmol) was added in portions. The reaction mixture was refluxed for 1 h and after cooling the precipitate was filtered. The solvent was evaporated and water (150 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organic phases were washed with water (3×100 mL) and brine (100 mL). Drying of the organic phase was performed with magnesium sulfate. The evaporation of the solvent gave crude product as a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give 2-(4-amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (23 g, 75%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.73-6.61 (m, 3H), 3.94-3.78 (m, 6H), 3.53 (t, J=7.7 Hz, 1H), 1.94-1.85 (m, 1H), 1.65-1.56 (m, 1H), 1.52-1.43 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.64-0.58 (m, 2H), 0.53-0.47 (m, 2H), 0.36-0.33 (m, 2H), 0.24-0.21 (m, 2H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 174.6, 146.4, 135.3, 129.3, 120.5, 114.6, 111.2, 73.1, 69.0, 49.2, 42.7, 25.8, 22.6, 22.4, 10.4, 9.8, 3.2.

Step 6 2-(4-Amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (16.3 g, 49.1 mmol) was dissolved in chloroform (200 mL) and N-chlorosuccinimide (5.3 g, 0.75 equiv, 39.6 mmol) was added. The reaction mixture was refluxed for 1 h and after cooling treated with 10% potassium carbonate solution (100 mL). The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were dried over magnesium sulfate. Evaporation of the solvent gave the crude product as a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give 2-(4-amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (5 g, 36%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.85 (s, 1H), 6.66 (s, 1H), 3.95-3.80 (m, 4H), 3.49 (t, J=7.7 Hz, 1H), 1.94-1.82 (m, 1H), 1.63-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.66-0.58 (m, 2H), 0.53-0.47 (m, 2H), 0.37-0.32 (m, 2H), 0.25-0.20 (m, 2H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 174.2, 146.8, 132.6, 128.7, 120.6, 118.3, 109.4, 73.6, 69.3, 49.0, 42.6, 25.9, 22.6, 22.4, 10.4, 9.8, 3.3.

Step 7 2-(3-Chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(4-Amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (5.0 g, 13.7 mmol) was dissolved in a mixture of EtOH/H₂O/H₂SO₄ (96%) (65 mL/100 mL/2.5 mL) and the reaction mixture was cooled down to 0° C. A solution of NaNO₂ (0.95 g, 13.7 mmol) in water (5 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 30 min. A solution of KI (7.0 g, 42.2 mmol) in water (20 mL) was added dropwise at 0° C. The reaction mixture was heated to 50-60° C. for 2.5 h. The reaction mixture was extracted with EtOAc (3×50 mL). The organic layers were combined and washed with 10% sodium thiosulfate solution (30 mL) followed by brine (30 mL). The organic phase was dried over MgSO₄ and the solvent evaporated to give a crude brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(3-Chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (4.0 g, 62%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.07 (s, 1H), 6.66 (s, 1H), 3.95-3.80 (m, 4H), 3.58 (t, J=7.7 Hz, 1H), 1.96-1.89 (m, 1H), 1.66-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.91 (d, J=6.6 Hz, 6H), 0.67-0.61 (m, 2H), 0.56-0.50 (m, 2H), 0.45-0.40 (m, 2H), 0.26-0.21 (m, 2H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.2, 159.2, 141.6, 139.4, 121.4, 109.8, 90.4, 74.0, 69.7, 49.4, 42.5, 26.0, 22.6, 22.3, 10.2, 9.8, 3.3.

Step 8 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.27 g, 0.57 mmol) in DME (anhydrous, 10 mL) under argon atmosphere were added 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,2,5]oxadiazole (0.15 g, 0.61 mmol), CsF (0.2 g, 1.32 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.021 g, 0.029 mmol, need 0.06 mmol to complete the reaction!). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture water/EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO₄, then evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography using Heptane-EtOAc (20:1-9:1) to give 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.11 g, 41%) of as a yellowish oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.83 (d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 1H), 7.11 (s, 1H), 6.91 (s, 1H), 4.02-3.81 (m, 4H), 3.67 (t, J=7.7 Hz, 1H), 2.03-1.96 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.20-1.05 (m, 2H), 0.96 (d, J=6.3 Hz, 6H), 0.57-0.47 (m, 4H), 0.28 (br s, 2H), 0.19 (br s, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.4, 157.0, 149.2, 148.3, 142.0, 138.7, 135.4, 133.5, 126.4, 121.6, 117.4, 114.9, 110.6, 73.4, 69.8, 49.8, 42.8, 26.1, 22.5, 22.4, 10.0, 9.8, 3.3, 3.1

Step 9 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid

2-(4-Benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.11 g, 0.23 mmol) was dissolved in a mixture of EtOH/H₂O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄ and evaporated under reduced pressure to give 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid as a yellow oil (0.068 g, 70%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.40 (br s, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.62 (s, 1H), 7.19 (d, J=9.3 Hz, 1H), 6.97 (s, 1H), 6.73 (s, 1H), 3.67 (d, J=6.6 Hz, 2H), 3.52 (t, J=7.7 Hz, 1H), 1.90-1.81 (m, 1H), 1.62-1.53 (m, 1H), 1.50-1.39 (m, 1H), 0.98-0.68 (m, 1H), 0.81 (d, J=6.1 Hz, 6H), 0.37-0.31 (m, 2H), 0.15-0.10 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.1, 157.1, 149.1, 148.3, 141.0, 138.6, 135.3, 133.7, 126.8, 121.6, 117.4, 115.0, 110.9, 73.4, 49.4, 41.9, 25.9, 22.6, 22.3, 10.0, 3.1.

Example 2995 2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid

Step 1 2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.18 g, 0.38 mmol) in DME (anhydrous, 10 mL) under argon atmosphere were added 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,2,5]thiodiazole (0.15 g, 0.57 mmol), CsF (0.14 g, 0.92 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.02 g, 0.027 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The combined organic phases were dried over MgSO₄ and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.08 g, 50%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.83 (d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 1H), 7.11 (s, 1H), 6.91 (s, 1H), 4.02-3.81 (m, 4H), 3.67 (t, J=7.7 Hz, 1H), 2.03-1.96 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.20-1.05 (m, 2H), 0.96 (d, J=6.3 Hz, 6H), 0.57-0.47 (m, 4H), 0.28 (br s, 2H), 0.19 (br s, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.5, 157.1, 154.7, 154.0, 141.4, 136.8, 133.7, 132.9, 126.9, 122.8, 121.6, 120.0, 110.8, 73.3, 69.7, 49.7, 42.7, 26.1, 22.5, 22.5, 10.0, 9.8, 3.3, 3.1.

Step 2 2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid

2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.08 g, 0.19 mmol) was dissolved in a mixture of EtOH and H₂O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄ and evaporated under reduced pressure to give 2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid as a yellow oil (0.038 g, 55%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.02 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.68 (t, J=7.6 Hz, 1H), 2.04-1.96 (m, 1H), 1.78-1.69 (m, 1H), 1.63-1.55 (m, 1H), 1.10-1.00 (m, 1H), 0.97 (d, J=6.4 Hz, 6H), 0.50-0.39 (m, 2H), 0.22-0.12 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.1, 157.2, 154.6, 154.0, 140.5, 136.7, 134.0, 132.9, 127.8, 122.9, 121.6, 120.1, 111.0, 73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.

Example 1904 2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid

Step 1 2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.09 g, 0.19 mmol) in DME (anhydrous, 10 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (0.04 g, 0.2 mmol), CsF (0.07 g, 0.46 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.06 g, 0.08 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO₄, then evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(2-chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.063 g, 70%) as a yellowish oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.66 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.88 (s, 1H), 4.01-3.86 (m, 2H), 3.77 (d, J=6.6 Hz, 2H), 3.65 (t, J=7.9 Hz, 1H), 2.04-1.95 (m, 1H), 1.71-1.62 (m, 1H), 1.59-1.48 (m, 1H), 1.20-1.02 (m, 2H), 0.96-0.94 (m, 6H), 0.56-0.46 (m, 4H), 0.27-0.25 (m, 2H), 0.16-0.15 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.5, 157.0, 141.2, 138.9, 133.6, 130.8 (two signals), 127.8, 124.5 (q), 124.3 (q, ¹J_(CF)=271.0 Hz), 121.6, 111.0, 73.3, 69.7, 49.6, 42.7, 26.1, 22.6, 22.4, 10.0, 9.8, 3.3, 3.1.

Step 2 2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid

2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.06 g, 0.12 mmol) was dissolved in a mixture of EtOH and H₂O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5 and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄ and evaporated under reduced pressure to give 2-(2-chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid as a yellowish solid (0.046 g, 85%). M.p.=115-116° C. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.67 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.85 (s, 1H), 3.77 (d, J=6.4 Hz, 2H), 3.65 (t, J=7.7 Hz, 1H), 2.04-1.94 (m, 1H), 1.75-1.66 (m, 1H), 1.60-1.52 (m, 1H), 1.15-0.89 (m, 1H), 0.95 (d, J=6.4 Hz, 6H), 0.54-0.40 (m, 2H), 0.20-0.10 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.0, 157.1, 140.3, 138.8, 133.8, 130.8, 129.3 (q), 128.2, 124.6, 124.3 (q, ¹J_(CF)=271.0 Hz), 121.6, 111.2, 73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.

Example 3200 2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid

Step 1 2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.32 g, 0.67 mmol) in DME (anhydrous, 20 mL) under argon atmosphere were added 4-chlorophenylboronic acid (0.13 g, 0.83 mmol), CsF (0.24 g, 1.58 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.05 g, 0.07 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO₄ and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.26 g, 87%) as a yellowish oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.37 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 7.07 (s, 1H), 6.86 (s, 1H), 3.96-3.89 (m, 2H), 3.76 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.7 Hz, 1H), 2.04-1.95 (m, 1H), 1.71-1.48 (m, 2H), 1.21-1.00 (m, 2H), 0.94 (d, J=6.3 Hz, 6H), 0.55-0.48 (m, 4H), 0.27-0.15 (m, 4H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.5, 157.1, 140.8, 133.7, 133.5, 133.0, 131.8, 128.1, 127.8, 121.5, 111.1, 73.2, 69.6, 49.6, 42.6, 26.1, 22.6, 22.5, 10.0, 9.8, 3.3, 3.0.

Step 2 2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid

2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.18 g, 0.36 mmol) was dissolved in a mixture of EtOH and H₂O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5 and the reaction mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over MgSO₄ and evaporated under reduced pressure to give 2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid as a yellowish solid (0.15 g, 93%). M.p.=52-53° C. ¹H NMR (300 MHz, CDCl₃/TMS): δ 10.60 (br s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.75 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 1.99-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.40 (m, 2H), 0.22-0.12 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.7, 157.2, 139.7, 134.0, 133.4, 133.1, 131.8, 128.5, 127.9, 121.6, 111.3, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.

Example 3201 4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid

Step 1 4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.53 g, 1.11 mmol) in DME (anhydrous, 20 mL) under argon atmosphere were added 4-chlorophenylboronic acid (0.25 g, 1.30 mmol), CsF (0.41 g, 2.70 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.24 g, 0.33 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO₄ and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 4-methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid cyclopropylmethyl ester (0.37 g, 70%) as a yellowish oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.48-7.42 (m, 2H), 7.17-7.14 (m, 2H), 7.07 (s, 1H), 6.86 (s, 1H), 4.07-3.87 (m, 2H), 3.78 (d, J=6.3 Hz, 2H), 3.64 (t, J=7.7 Hz, 1H), 2.03-1.93 (m, 1H), 1.70-1.49 (m, 2H), 1.21-1.00 (m, 2H), 0.95-0.93 (m, 6H), 0.56-0.49 (m, 4H), 0.27-0.19 (m, 4H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.4, 156.9, 141.3, 134.9, 133.6, 132.5, 131.6, 131.2, 129.9, 129.5, 126.6, 121.5, 110.8, 73.2, 69.6, 49.6, 42.6, 26.1, 22.6, 22.4, 10.0, 9.8, 3.3, 3.1.

Step 2 4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid

4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid cyclopropylmethyl ester (0.37 g, 0.75 mmol) was dissolved in a mixture of EtOH and

H₂O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over MgSO₄ and evaporated under reduced pressure to give 4-methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid as a white solid (0.30 g, 90%). M.p.=118-119° C. ¹H NMR (300 MHz, CDCl₃/TMS): δ 9.70 (br s, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.53 (dd, J=8.2, 1.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.78 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 2.02-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.47 (m, 2H), 0.24-0.16 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.4, 157.0, 140.3, 134.8, 133.9, 132.5, 131.6, 131.3, 129.9, 129.6, 127.0, 121.5, 111.1, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.

Example 1976 2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-4-methyl-pentanoic acid

Step 1 5-Fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene

To a solution of 2,2,2-trifluoroethanol (28.2 g, 282.0 mmol) in toluene (120 mL) n-BuLi (1.6 M in hexane, 8.0 g, 80 mL, 125.0 mmol) was added at 0° C. and the reaction mixture warmed up to 25° C. A solution of 1,3,5-trifluoronitrobenzene (10.0 g, 56.5 mmol) in toluene (50 mL) was added dropwise. The reaction mixture was refluxed for 30 h and then poured into water (100 mL). The reaction mixture was extracted with EtOAc (3×100 mL). The organic layers were combined and dried over MgSO₄. The solvent was evaporated under reduced pressure to give 5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene as a brown oil (18.0 g, 95%). The product was used for the next step without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.47 (d, J=9.4 Hz, 2H), 4.40 (q, J=8.0 Hz, 4H).

Step 2 2-[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethyl ester

To a solution of diethyl malonate (18.0 g, 114.9 mmol) in DMF (50 mL) was added sodium hydride (60% in mineral oil, 3.0 g, 125.0 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h and a solution of 5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene (18.0 g, 53.4 mmol) in DMF (30 mL) was added dropwise. The reaction mixture was heated 100° C. for 24 h. After cooling the reaction mixture was poured into water (300 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO₄). Evaporation of the solvent under reduced pressure gave 2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethyl ester as a brown oil (20.8 g, 80%). The crude product was used for the next step without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.91 (s, 2H), 4.62 (s, 1H), 4.48 (q, J=8.0 Hz, 4H), 4.28-4.16 (m, 4H), 1.31-1.25 (m, 6H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 166.4, 149.2, 136.7, 132.3, 122.3 (q, ¹J_(CF)=276.6 Hz), 109.5 (two signals), 67.0 (q, ²J_(CF)=36.7 Hz), 61.4, 41.6, 14.0.

Step 3 [4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl ester

Crude 2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethyl ester (20.8 g, 43.6 mmol) was dissolved in a mixture of AcOH/12 N HCl (150 mL/150 mL) and the reaction mixture was refluxed for 16 h. The solvent was evaporated and water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL). The organic layers were combined, washed with water (3×100 mL), and dried over MgSO₄. The solvent was evaporated under reduced pressure to give a brown solid, which was washed with a mixture of Heptane/Et₂O (100 mL/100 mL) to give [4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester as a solid (10.0 g, 57%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.71 (s, 2H), 4.45 (q, J=7.7 Hz, 4H), 4.18 (q, J=7.2 Hz, 2H), 3.63 (s, 2H), 1.28 (t, J=7.1 Hz, 6H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 169.7, 149.6, 138.5, 132.4, 122.4 (q, ¹J_(CF)=277.6 Hz), 109.4 (two signals), 67.0 (q, ²J_(CF)=37.2 Hz), 61.6, 41.4, 14.2.

Step 4 [4-Amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl ester

[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (10.0 g, 24.7 mmol) was dissolved in EtOH (200 mL) and hydrogenated at 50 psi, 25° C. for 16 h in the presence of Pd—C catalyst (10%, 1 g). The catalyst was filtered off and the solvent evaporated to give a crude brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give [4-amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester as a yellow oil (8.3 g, 90%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.52 (s, 2H), 4.37 (q, J=8.0 Hz, 4H), 4.14 (q, J=7.2 Hz, 2H), 3.90 (br s, 2H), 3.48 (s, 2H), 1.25 (t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 171.4, 145.0, 126.3, 123.2, (q, ¹J_(CF)=277.6 Hz), 122.6, 110.0, 109.8 (two signals), 66.8 (q, ²J_(CF)=35.5 Hz), 61.0, 41.0, 14.2.

Step 5 [4-Iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl ester

[4-Amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (7.1 g, 18.9 mmol) was dissolved in MeCN (50 mL) and p-TsOH×H₂O (11.0 g, 57.9 mmol) was added. The reaction mixture was cooled down to −15° C. and NaNO₂ (1.6 g, 23.2 mmol) in water (1 mL) was added. The reaction mixture was stirred at −15° C. for 0.5 h; then a solution of KI (15.0 g, 93.8 mmol) in water (10 mL) was added. The reaction mixture was stirred at −15° C. for additional 0.5 h and quenched with 1 N NaHCO₃ solution to pH 9-10. After addition of 10% NaHSO₃ solution (20 mL), the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with saturated NaCl solution, dried (MgSO₄) and evaporated to give crude a brown oil (9.0 g), which was purified by gradient column chromatography on silica gel eluting with Heptane-EtOAc (9:1-3:1) to give [4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester as a white solid (3.8 g, 41%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.53 (s, 2H), 4.40 (q, J=8.0 Hz, 4H), 4.16 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 1.26 (t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 170.3, 157.7, 136.7, 122.8 (q, ¹J_(CF)=277.6 Hz), 108.9 (two signals), 78.3, 67.0 (q, ²J_(CF)=36.0 Hz), 61.3, 41.2, 14.2.

Step 6 [2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-acetic acid ethyl ester

To a solution of [4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (0.8 g, 1.65 mmol) in DME (anhydrous, 15 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (0.4 g, 2.10 mmol), CsF (0.6 g, 3.95 mmol), and Pd(PPh₃)₄ (0.3 g, 0.26 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO₄ and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give [2,6-bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-acetic acid ethyl ester (0.54 g, 70%) as a yellowish oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.64 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 6.68 (s, 2H), 4.28-4.16 (6H), 3.63 (s, 2H), 1.29 (t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 170.6, 155.3, 136.1, 135.5, 131.0, 129.4, 129.0, 124.4 (q, ³J_(CF)=3.9 Hz), 124.2, 122.9, 119.0, 109.2 (two signals), 66.5 (q, ²J_(CF)=35.5 Hz), 61.3, 41.5, 14.2.

Step 7 2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-4-methyl-pentanoic acid

[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-acetic acid ethyl ester (0.52 g, 1.03 mmol) was dissolved in anhydrous DMF (5 mL) and sodium hydride (60% in oil, 0.05 g, 2.08 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 20 min and isobutyl bromide (0.15 g, 1.09 mmol) was added. The reaction mixture was stirred for 1 h at the same temperature and at 25° C. for 15 min., followed by addition of saturated ammonium chloride solution (10 mL). The reaction mixture was extracted with ethyl acetate (2×20 mL) and the combined organic phases were washed with water (3×20 mL), saturated sodium chloride solution (10 mL) and dried over magnesium sulfate. Evaporation gave the crude yellow oil (0.56 g), which was purified by silica gel column chromatography with Heptane/EtOAc to give a white solid (0.24 g). The resulting solid was dissolved in EtOH (10 mL), and H₂O (1 mL) and potassium hydroxide (0.2 g) were added. The reaction mixture was refluxed for 2 h and solvent evaporated. Then, 6 N HCl was added to adjust the pH to 3-5 and the mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄ and evaporated to give 2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-4-methyl-pentanoic acid as a white solid (0.2 g, 40%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.65 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 6.72 (s, 2H), 4.24 (q, J=8.0 Hz, 4H), 3.69 (t, J=7.7 Hz, 1H), 2.03-1.96 (m, 1H), 1.76-1.67 (m, 1H), 1.60-1.52 (m, 1H), 0.96 (d, J=6.3 Hz, 6H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.3, 155.4, 140.6, 135.3, 130.9, 129.6, 129.1, 124.5 (q, ³J_(CF)=4 Hz), 124.2 (q, ¹J_(CF)=272 Hz), 122.9 (q, ¹J_(CF)=278 Hz), 119.8, 107.9, 66.5 (q, ²J_(CF)=36 Hz), 49.7, 42.2, 25.9, 22.6, 22.3.

Example 2420 2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid

Step 1 4-Fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene

To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89 mol) and 2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was added sodium hydroxide (90.5 g, 2.26 mol) in portions over 30 min to keep the temperature between 30 and 40° C. After the temperature had dropped to 30° C., the reaction mixture was heated to 45-50° C. using an oil bath for additional 16 h. After cooling, water (500 mL) and 2.5 NH₂SO₄ (200-300 mL, for adjustment of pH to 5) were added and the organic layer was separated. The water layer was extracted with EtOAc (2×300 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and dried over magnesium sulfate. The solvent was evaporated to give a yellow oil, which solidified after 30 min to give a yellowish solid (450.0 g, quantitative). The crude product was used in the next step without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J=7.7 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 165.0 (d, ¹J_(CF)=259.6 Hz), 152.3 (d, ³J_(CF)=13.1 Hz), 128.2 (d, ³J_(CF)=11.9 Hz), 122.4 (d, ¹J_(CF)=273.4 Hz), 110.1 (d, ²J_(CF)=22.5 Hz), 105.9 (q, ¹J_(CF)=242.6 Hz), 104.3 (d, ²J_(CF)=26.1 Hz), 67.6 (q, ¹J_(CF)=36.7 Hz).

Step 2 [4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid

-   -   Potassium hydroxide (>85%, 176 g, >2.67 mmol) was added to a         solution of 4-fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene         (412 g, ˜90% purity, 1.56 mmol) and diethyl malonate (503.0 g,         3.14 mmol) in DMSO (700 mL) in portions to keep the temperature         at ˜40° C. The reaction mixture became deep red in color. The         reaction mixture was stirred at 40° C. overnight. Monitoring was         performed by TLC (EtOAc:Hept., 1:3).

Acetic acid (1 L) was added to the warm reaction mixture followed by a mixture of concentrated sulfuric acid (325 mL) in water (1 L) in one portion. A precipitate, which was formed initially, dissolved at the end of the addition. Effective stirring was required for this reaction. The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and EtOAc (1000 mL) and water (1000 mL) were added. The organic layer (bottom layer!) was separated. The aqueous solution was extracted with EtOAc (500 mL), the organic phases were combined, washed with water (3×2000 mL), brine (500 mL), and dried over MgSO₄ with charcoal. The solvent was evaporated and the solid residue was washed by stirring with heptane/EtOAc (20:1, 500 mL). The solid was filtered and dried in vacuum. The yield of 2-(4-nitro-3-(2,2,2-trifluoro-ethoxy)phenyl)acetic acid was 256 g (65%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.80 (d, J=8.3 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J=8.3 Hz, 1H), 5.07 (s, 1H), 4.67 (q, J=8.2 Hz, 2H), 3.70 (s, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 175.0, 151.5, 144.0, 140.3, 126.4, 125.0, 122.2 (d, ¹J_(CF)=273.0 Hz), 118.0, 67.6 (q, ¹J_(CF)=36.0 Hz), 42.5.

Step 3 [4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid methyl ester

Concentrated sulfuric acid (50 mL) was added slowly to a solution of 2-(4-nitro-3-(2,2,2-trifluoro-ethoxy)phenyl)acetic acid (180 g, 0.64 mol) in MeOH (500 mL). The reaction mixture was stirred at room temperature overnight. The methanol was evaporated and EtOAc (500 mL) was added. The solution was washed with water (2×200 mL) and brine and dried over MgSO₄. The solvent was evaporated, the solid residue was stirred with heptane (200 mL), and the solid was filtered. Yield 182.2 g (96%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.82 (d, J=8.7 Hz, 1H), 7.07-7.05 (m, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.67 (s, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 170.1, 150.4, 141.2, 139.4, 125.9, 123.9, 122.6 (d, ¹J_(CF)=277.6 Hz), 117.5, 67.6 (q, ¹J_(CF)=36.7 Hz), 52.4, 41.0.

Step 4 3-Cyclobutyl-2-[4-nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic acid methyl ester

[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid methyl ester (33 g, 94.5 mmol) and (bromomethyl)cyclobutane (17 g, 114.1 mmol) were mixed in DMSO (50 mL) and KOH (6.4 g, 114.1 mmol) was added in portions over 15 min. The reaction mixture was stirred for 16 h and water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO₄ and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography using Heptane-EtOAc (9:1-4:1) to give 15 g (40%) of the product as a yellow oil. (The synthesis was repeated with temperature kept at 40° C. over 16 h to give the product in quantitative yield). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.86 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 2H), 4.50 (q, J=7.7 Hz, 2H), 3.68 (s, 3H), 3.55 (t, J=7.3 Hz, 1H), 2.22-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.55 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 172.9, 150.5, 146.4, 139.4, 126.0, 122.7, 122.6 (d, ¹J_(CF)=277.6 Hz), 116.0, 67.5 (q, ¹J_(CF)=36.7 Hz), 52.3, 49.6, 40.7, 33.9, 28.2, 27.9, 18.4.

Step 5 2-[4-Amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester

A solution of the 3-cyclobutyl-2-[4-nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic acid methyl ester (15 g, 36.0 mmol) in EtOH (150 mL) was hydrogenated at 50 psi and 25° C. for 16 h in the presence of Pd—C catalyst (10%, 1.5 g). On the next day, the catalyst was filtered off and the solvent evaporated to give the crude product (12.3 g, 88%) as a yellow oil, which was used without purification for the next step. ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.79-6.73 (m, 2H), 6.66 (d, J=8.0 Hz, 1H), 4.36 (q, J=8.3 Hz, 2H), 3.80 (br s, 2H), 3.63 (s, 3H), 3.35 (t, J=7.7 Hz, 1H), 2.20-1.86 (m, 4H), 1.85-1.70 (m, 3H), 1.67-1.51 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 174.7, 146.7, 135.7, 129.1, 123.3 (d, ¹J_(CF)=277.6 Hz), 122.7, 115.4, 112.2, 66.4 (q, ¹J_(CF)=35.4 Hz), 51.9, 48.9, 40.8, 34.0, 28.3, 28.1, 18.5.

Step 6 2-[4-Amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester

To a solution of the 2-[4-amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester (12.3 g, 31.8 mmol) in chloroform (150 mL) was added N-bromosuccinimide (7 g, 39.3 mmol). The reaction mixture was stirred at 25° C. for 16 h and a mixture of water and methylene chloride (100 mL/100 mL) was added. The reaction mixture was extracted with methylene chloride (2×50 mL) and the organic phases were separated. The combined organic phases were dried over MgSO₄ and evaporated to give a crude yellow oil, which was purified by a short silica gel column chromatography eluting with heptane-EtOAc (4:1) to give the product (13.9 g, 94%) as a yellowish oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.06 (d, J=1.1 Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 4.37 (q, J=8.0 Hz, 2H), 4.21 (br s, 2H), 3.64 (s, 3H), 3.31 (t, J=7.7 Hz, 1H), 2.20-1.89 (m, 4H), 1.81-1.75 (m, 3H), 1.67-1.51 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 174.2, 144.6, 134.4, 128.9, 125.7, 123.0 (d, ¹J_(CF)=277.6 Hz), 110.9, 108.7, 66.5 (q, ¹J_(CF)=36.0 Hz), 52.0, 48.6, 40.7, 33.9, 28.3, 28.0, 18.5.

Step 7 2-[6-Amino-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester

To a solution of 2-[4-amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester (13.8 g, 29.6 mmol) in DME (anhydrous, 100 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (6.8 g, 35.8 mmol), CsF (11 g, 72.3 mmol), and Pd(PPh₃)₄ (3.4 g, 2.94 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). On the next day, a mixture water and EtOAc (100 mL/100 mL) was added and the layers were separated. The organic phase was dried over MgSO₄ and evaporated to give a crude yellow oil, which was purified by a short silica gel column chromatography by use of Heptane-EtOAc (4:1) to give the product (14.7 g, 94%) as a yellowish oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 6.78 (dd, J=9.6, 1.4 Hz, 2H), 4.43 (q, J=8.0 Hz, 2H), 3.95 (br s, 2H), 3.66 (s, 3H), 3.39 (t, J=7.7 Hz, 1H), 2.25-2.07 (m, 2H), 2.03-1.91 (m, 2H), 1.88-1.75 (m, 3H), 1.69-1.52 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 174.6, 144.8, 133.1, 129.2, 128.6, 126.3, 125.7 (q, ³J_(CF)=3.6 Hz), 123.8, 123.3 (q, ¹J_(CF)=277.6 Hz), 111.4, 66.5 (q, ¹J_(CF)=35.4 Hz), 52.0, 49.0, 40.9, 34.1, 28.3, 28.1, 18.5.

Step 8 2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester

To a solution of 2-[6-amino-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester (14.7 g, 27.7 mmol) in a mixture of MeCN and H₂O (120 mL/120 mL), concentrated HCl (25 mL) was added. The reaction mixture was cooled down to 0-5° C. and a solution of NaNO₂ (2.9 g, 42.0 mmol) in water (3 mL) was added dropwise. The reaction mixture was stirred at 0-5° C. for 40 min and CuCl (I) (27 g, 272.7 mmol) was added at once. The reaction mixture was heated at 50° C. for additional 3 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (200 mL) and brine (100 mL). The organic phase was dried over MgSO₄ and evaporated to give the product (14.5 g, 95%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 6.98 (dd, J=6.1, 1.6 Hz, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.48 (t, J=7.7 Hz, 1H), 2.20-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.52 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.6, 153.5, 142.2, 141.0, 138.9, 129.7, 125.0 (q, ³J_(CF)=3.6 Hz), 124.8, 124.0 (q, ¹J_(CF)=271.6 Hz), 126.6 (q, ¹J_(CF)=278.8 Hz), 121.4, 114.0, 67.3 (q, ¹J_(CF)=35.4 Hz), 52.2, 49.3, 40.8, 34.0, 28.3, 28.0, 18.5.

Step 9 2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid

To a solution of the 2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester (8.0 g, 14.5 mmol) in a mixture of the EtOH (100 mL) and H₂O (15 mL) was added potassium hydroxide (10 g, 178.5 mmol). The reaction mixture was refluxed for 3 h and the solvent evaporated. Then, 6 N HCl was added to adjust the pH to 3-5 and the mixture was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO₄ and evaporated to give 2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid as a white solid (7.0 g, 90%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 6.98 (s, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.49 (t, J=7.7 Hz, 1H), 2.27-2.13 (m, 2H), 2.06-1.73 (m, 5H), 1.71-1.52 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.1, 153.6, 142.1, 141.2, 138.0, 129.7, 125.0 (q, ³J_(CF)=3.6 Hz), 124.9, 124.0 (q, ¹J_(CF)=262.5 Hz), 123.0 (q, ¹J_(CF)=277.6 Hz), 121.8, 114.3, 67.3 (q, ¹J_(CF)=36.0 Hz), 49.3, 40.3, 33.9, 28.3, 28.0, 18.5.

Example 415 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1 Ethyl 2-(3-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.076 molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol). The mixture was brought to reflux and sulfuryl chloride (6.8 ml, 0.846 mol) dissolved in DCM (50 mL) was slowly added under over 10 min. The reaction mixture was refluxed further for 5 h, upon which the reaction mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with 10% NaHCO₃ solution and water. The organic layer was dried over Na₂SO₄, filtered and evaporated under vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g).

Step 2 Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate

To a stirred solution of compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (11 g, 51 mmol) in 200 ml of CCl₄, was slowly added bromine (8.22 g, 51 mmol) as a solution CCl₄ (100 ml) at 0° C. over a period of 30 min. The reaction mixture was stirred for a further 30 min at 0° C. Upon which the reaction mixture was poured onto crushed ice and extracted with DCM (2×100 mL). The combined organic layers were washed with water followed by 10% sodium bisulfite solution, dried over Na₂SO₄ filtered and evaporated under reduced pressure to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (12.2 g) as a white solid in 80% yield. ¹HNMR (CDCl₃): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs, 1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).

Step 3 Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (2 g, 6.8 mmol), potassium carbonate (2.35 g, 17.0 mmol) in dry DMF (20 mL), was slowly added trifluoro ethyl iodide (8.58 g, 4.0 mL, 40.8 mmol) at room temperature, the reaction mixture was slowly heated to 100° C. and heating was continued for 4 h. Upon which the reaction mixture was poured onto water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄ and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc) to gave compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750 g, 30% yield). ¹H NMR (CDCl₃, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);

Step 4 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate

A mixture of 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750 g, 2.0 mmol), 4-trifluoromethyl phenylboronic acid (0.567 g, 3.0 mmol), Pd (PPh₃)₄ (0.231 g, 0.2 mmol), cesium fluoride (0.604 g, 4.0 mmol) in DME (10 ml) was stirred overnight at 100° C., upon which the precipitates were removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water followed by brine and dried over Na₂SO₄. The crude residue was purified by flash column chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.525 g, 73.6%) as an off white solid.

Step 5 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (1.0 g, 2.27 mmol) was dissolved in anhydrous DMF (80 mL), NaH (60% wt. in paraffin oil, 0.109 g, 2.72 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature, upon which cyclopropyl methyl bromide (0.24 mL, 2.5 mmol) was added in a dropwise manner at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. upon which saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over Na₂SO₄, filtered and evaporated under reduced pressure to give colorless oil, which was purified by flash column chromatography to yield compound ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.68 g).

Step 6 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.68 g, 0.4 mmol) and lithium hydroxide monohydrate (100 mg, 4.6 mmol) in a MeOH/THF/Water solvent mixture (15 ml/15 ml/15/ml) was stirred for 3 h at room temperature. After completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid in 88% yield (0.4 g). ¹H-NMR (CDCl₃, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.43 (s, 1H); 7.24 (s, 1H); 3.98 (q, 2H); 3.72 (t, 1H); 1.94 (m, 1H), 1.78 (m, 1H); 0.71 (m, 1H), 0.46 (m, 2H), 0.02-0.19 (m, 2H).

Example 1269 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylic acid Step 1 Ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(Trifluoromethyl)biphenyl-3-yl)-cyclo butane carboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (1.5 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,3-dibromopropane (0.757 g, 3.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred for an additional 1 h at 0° C. and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo butane carboxylate (400 mg).

Step 2 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylic acid

A mixture of ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo butane carboxylate (400 mg, 0.83 mmol) and lithium hydroxide monohydrate (0.2 g, 8.3 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylic acid in 88% yield (0.21 g). ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.39 (s, 1H); 7.26 (s, 1H); 3.98 (q, 2H); 2.86 (m, 2H); 2.52 (m, 2H); 2.16 (m, 1H), 1.91 (m, 1H).

Example 419 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylic acid Step 1 Ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo pentane carboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.8 g, 1.81 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.109 g, 4.5 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,4-dibromobutane (0.432 g, 1.99 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. upon which saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo pentane carboxylate (400 mg) as a thick liquid.

Step 2 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylic acid

A mixture of compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo pentane carboxylate (100 mg, 0.21 mmol) and lithium hydroxide monohydrate (96 mg, 2.1 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylic acid (0.05 g). ¹H-NMR (CDCl₃, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.68 (m, 2H); 1.94 (m, 2H); 1.78 (m, 4H).

Example 3202 4-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylic acid Step 1 Ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.4 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1-iodo-2-(2-iodoethoxy)ethane (1.2 g, 3.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg).

Step 2 4-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylic acid

A mixture of ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.188 g, 7.8 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). Combined organic layer was washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylic acid (100 mg). ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 3.61 (t, 2H); 2.53 (dd, 2H); 1.99 (m, 2H).

Example 3203 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylic acid Step 1 Ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.113 g, 2.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 3,3-dimethyl-1,5-dibromopentane (0.322 g, 1.25 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate (230 mg).

Step 2 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylic acid

A mixture of compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate (200 mg, 0.37 mmol) and lithium hydroxide monohydrate (88 mg, 3.7 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylic acid in 67% yield (150 mg). ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.88 (m, 2H); 1.41 (m, 4H), 0.98 (s, 3H), 0.91 (s, 3H).

Example 1270 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexane carboxylic acid Step 1 Ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.113 g, 2.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,5-dibromopentane (0.19 g, 1.24 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate (0.37 g) as a thick liquid.

Step 2 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexane carboxylic acid

A mixture of ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate (0.37 g, 0.72 mmol) and lithium hydroxide monohydrate (0.174 g, 7.28 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexane carboxylic acid (0.25 g) as a white solid. ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.55 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.52-1.81 (m, 6H); 1.33 (m, 2H).

Example 1271 5-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylic acid Step 1 Ethyl 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.6 g, 1.36 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.136 g, 3.4 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,1-bis(bromomethyl)cyclopropane (0.482 g, 1.4 mmol, for preparation see J. Org. Chem. 1993, 58, 4122-26) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate (150 mg) as a low melting solid.

Step 2 5-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylic acid

A mixture of ethyl 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate (0.5 g, 0.9 mmol) and lithium hydroxide monohydrate (0.415 g, 9.88 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylic acid (0.29 g). ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41 (s, 1H); 7.21 (s, 1H); 3.98 (q, 2H); 2.95 (d, 2H); 2.75 (d, 2H), 0.58 (t, 2H), 0.48 (t, 2H).

Example 1268 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid Step 1 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.6 g, 0.49 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.039 g, 1.69 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and cyclobutylmethyl bromide (0.223 g, 1.49 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄ The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate (0.25 g) as a colorless liquid.

Step 2 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate (0.25 g, 0.49 mmol) and lithium hydroxide monohydrate (0.206 g, 4.9 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid (0.106 g) as a white solid. ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41 (s, 1H); 7.18 (s, 1H); 3.98 (q, 2H); 3.51 (t, 1H); 2.15-2.28 (m, 2H); 1.55-2.15 (m, 7H).

Example 1272 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid Step 1 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.8 g, 1.8 mmol) was dissolved in anhydrous DMF (40 mL), NaH (60% wt. in paraffin oil, 0.052 g, 2.18 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and cyclopentyl bromide (0.298 g, 1.99 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate (0.4 mg) as a thick liquid.

Step 2 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate (400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.330 g, 7.87 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid (0.08 g). ¹H-NMR (CDCl₃, 400 MHz): 12.5 (s, 1H), 7.84 (d, 2H); 7.70 (d, 2H), 7.55 (s, 1H); 7.35 (s, 1H); 4.22 (q, 2H); 3.3.35 (d, 1H); 1.82 (m, 1H); 1.18-1.68 (m, 7H); 1.08 (m, 1H).

Example 3204 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoic acid Step 1 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.6 g, 1.36 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.039 g, 1.36 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and cyclopentyl bromide (0.283 g, 1.49 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate (0.29 g) as a colorless liquid.

Step 2 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate (400 mg, 0.719 mmol) and lithium hydroxide monohydrate (0.306 g, 7.29 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoic acid (0.1 g). ¹H-NMR (CDCl₃, 400 MHz): 7.55-7.78 (m, 4H); 7.42 (s, 1H), 7.18 (s, 1H); 6.92-7.16 (m, 4H); 3.98 (q, 2H); 3.84 (t, 1H); 3.41 (dd, 1H), 3.02 (dd, 1H).

Example 1905 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid

Step 1

2-(Cyclopropylmethoxy)-4-fluoro-1-nitrobenzene

Cyclopropyl methanol (15 g, 207 mmol) was added to a stirred suspension of NaH (60% in mineral oil, 8.37 g) in 200 mL THF over a period of 15 min at 0° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h at RT. The mixture was cooled to 0° C. and a solution of 2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was added in a drop wise manner. The reaction mixture was stirred at 0° C. for 2 h and then poured onto ice water. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure to give 22.0 g of 2-(cyclopropylmethoxy)-4-fluoro-1-nitrobenzene as an orange oil (86%).

Step 2 Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate

Diethyl malonate (9.8 g, 1.1 eq) was added to a stirred suspension of sodium hydride (60% in mineral oil, 2.09 g) in DMF (88 mL) over 15 min. at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq) in DMF (88 mL) was added drop wise at 0° C., and the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into ice water and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL) and brine (100 mL), dried (MgSO₄) and filtered. Evaporation of the volatiles under reduced pressure gave 10.0 g of crude product which was purified by chromatography over silica gel (hexane/EtOAc) gave of diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (7.0 g). ¹H-NMR (CDCl₃, 200 MHz): 0.4 (m, 2H), 0.71 (m, 2H), 1.3 (m, 1H), 1.3 (t, 6H), 3.96 (d, 2H), 4.25 (q, 4H), 4.5 (s, 1H), 7.02 (d, 1H), 7.18 (s, 1H), 7.81 (d, 2H).

Step 3 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid

Compound diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (10 g) was dissolved in 100 mL ethanol and cooled to 0° C., NaOH solution (4 eq) was added slowly to the reaction mixture for about 15 min. The reaction mixture was heated gently up to 60° C. for 5 h. Progress of the reaction was monitored by TLC analysis. After complete conversion of starting material solvent was evaporated under reduced pressure, residue dissolved in H₂O, acidified with 6N HCl to pH-2. Filtered the solid material washed with water, dried under reduced pressure to give 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (6.5 g) as a yellow solid. ¹H-NMR (CDCl₃, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H), 1.28 (m, 1H), 3.71 (s, 2H), 4.01 (d, 2H), 7.02 (d, 1H), 7.23 (s, 1H), 7.81 (d, 1H).

Step 4 Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate

2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (40 g, 143 mmol) was dissolved in 20% EtOH—HCl solution (200 ml) and refluxed for 3 h to convert the starting material to ester. The volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate (×2). The combined organic extracts were washed with water, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude material was purified by re crystallization to ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (38 g) as pale yellow solid.

Step 5 Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of compound ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH (100 mL), Pd(OH)₂ (2 g) was added and the mixture was reduced under an H₂ atmosphere for 6 h at room temperature. The mixture was filtered a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (7.5 g) as a thick liquid. ¹H-NMR (CDCl₃, 200 MHz): 0.38 (m, 2H), 0.61 (m, 2H), 1.23 (m, 1H), 1.23 (t, 3H), 3.51 (s, 2H), 3.80 (d, 2H), 4.16 (q, 2H), 6.72 (m, 3H).

Step 6 Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol) in dry CCl₄ (60 mL), NCS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic layers were dried over Na₂SO₄, filtered and the volatiles removed in vacuo. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg) as a yellow solid.

Step 7 Ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate

Ethyl-2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)-acetate (2.5 g, 10.0 mmol) was dissolved in a mixture of EtOH/H₂O/H₂SO₄ (96%) 200 mL/400 mL/10 mL at 0° C. A solution of NaNO₂ (3.2 g, 1.16 eq) in water (40 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min at the same temperature. A solution of KI (30 g, 30.1 mmol) in water (80 mL) was added drop wise at 0° C. The reaction mixture was heated to 50° C. for 2.5 h upon which the volatiles were removed under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with 10% sodium thiosulfate (2×50 mL), water (300 mL) and brine (300 mL). The organic solution was dried over Na₂SO₄ and concentrated under reduced pressure to give a crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give the product ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate as a yellow oil (8.7 g).

Step 8 Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate

A mixture of compound ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd (PPh₃)₄ (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over NaSO₄, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (4.6 g) as a yellow oil. ¹H-NMR (CDCl₃, 200 MHz): 0.41 (m, 2H), 0.62 (m, 2H), 1.22 (t, 3H), 1.23 (m, 1H), 3.58 (s, 2H), 3.89 (d, 2H), 4.17 (q, 2H), 6.96 (m, 2H), 7.31 (s, 1H), 7.64 (m, 4H).

Step 9 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid

Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (1.1 g, 2.4 mmol) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.9 g) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and cyclopropyl methyl bromide (1.25 mL) was added drop wise at 0° C. The reaction mixture was stirred for an additional 1 h at 0° C. upon which saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered and the volatiles removed under reduced pressure to give 0.85 g of a colorless oil. The oil was dissolved in 10 mL of EtOH/H₂O (9:1, v/v) and (1.0 g) LiOH added. The reaction mixture was refluxed for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄ and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3 cyclopropylpropanoic acid (0.42 g) as a white solid, L-21-1 (56%). ¹H NMR (300 MHz, CDCl₃): δ 7.65 (d, 2H), 7.38 (d, 2H), 7.08 (s, 1H), 6.83 (s, 1H), 3.75 (d, 2H), 3.62 (t, 1H), 1.96 (m, 1H), 1.08 (m, 1H), 0.84 (m, 1H), 0.44 (m, 4H), 0.16 (m, 4H).

Example 1908 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclobutanecarboxylic acid

Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (0.5 g,) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.5 mL) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and upon which saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered and concentrated under reduced pressure to give 240 mg of a colorless oil. The oil was dissolved in 10 mL of EtOH/H₂O (9:1, v/v) and 0.42 g LiOH added. The reaction mixture was refluxed for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified via column chromatography over silica gel (hexane/EtOAc 9:1) to give 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclobutanecarboxylic acid (0.210 g) as a white solid (52% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.68 (d, 2H), 7.41 (d, 2H), 7.06 (s, 1H), 6.89 (s, 1H), 3.78 (d, 2H), 2.88 (m, 2H), 2.58 (m, 2H), 2.16 (m, 1H), 1.97 (m, 1H), 1.03 (m, 1H), 0.46 (m, 2H), 0.18 (m, 2H).

Example 1909 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclopentanecarboxylic acid

Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (0.5 g) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,4-dibromobutane (0.24 g) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered and concentrated under reduced pressure to give 380 mg of colorless oil. The oil was dissolved in 10 mL of EtOH/H₂O (9:1, vvl) and 1.0 g LiOH added. The reaction mixture was refluxed for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄ filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclopentanecarboxylic acid (0.210 g) as a white solid (60%). ¹H NMR (500 MHz, CDCl₃): δ 7.68 (d, 2H), 7.41 (d, 2H), 7.16 (s, 1H), 6.91 (s, 1H), 3.78 (d, 2H), 2.66 (m, 2H), 1.97 (m, 2H), 1.79 (m, 4H), 1.03 (m, 1H), 0.46 (d, 2H), 0.18 (d, 2H).

Example 2491 2-(6-Chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1 Ethyl 3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g, 17.9 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.475 g, 19.7 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and cyclopropylmethyl bromide (2.67 g, 19.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give ethyl 3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate (4 g) as a colorless oil.

Step 2 Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate

To a stirred solution of ethyl 3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate (4.0 g), in dry MeOH (100 mL), Pd(OH)₂ (2 g) was added and the mixture was reduced under an atmosphere of H₂ for 6 h at room temperature. The reaction mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate (3.5 g) as a thick liquid.

Step 3 Ethyl 2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropyl propanoate

To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate (3.0 g, 9.8 mmol) in dry CHCl₃ (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield the ethyl 2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropyl propanoate (1.5 g) as a yellow solid.

Step 4 Ethyl 2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of ethyl 2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropyl propanoate (2.8 g, 7.2 mmol), 4-trifluoromethylphenylboronic acid (2.05 g, 18.8 mmol), CsF (2.19 g, 14.5 mmol) and Pd (PPh₃)₄ (0.837 g, 0.72 mmol) in 30 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over NaSO₄, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (2.5 g) as a yellow oil.

Step 5 Ethyl 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

Ethyl 2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO₂ (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the mixture was concentrated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), the combined organic layers were washed with water (50 mL) followed by brine (50 mL), was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a crude black oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (1.1 g) as a yellow oil.

Step 6 2-(6-Chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (80 mg) was dissolved in 10 mL of MeOH/THF/H₂O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave compound 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid (45 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.71 (d, 2H), 7.54 (d, 2H), 6.95 (d, 1H), 6.87 (s, 1H), 3.97 (d, 2H), 3.64 (t, 1H), 2.55 (m, 2H), 1.96 (m, 1H), 1.08 (m, 1H), 0.84 (m, 1H), 0.44 (m, 4H), 0.16 (m, 4H).

Example 2494 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid

Step 1 Ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g, 17.9 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 1.43 g, 35.9 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.91 mL, 17.9 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8 g) as a colorless oil.

Step 2 Ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8 g), in dry MeOH (100 mL), Pd(OH)₂ (1.2 g) was added and the reaction mixture was reduced under an atmosphere of H₂ for 6 h at room temperature. The reaction mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g) as a thick liquid.

Step 3 Ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g, 8.3 mmol) in dry CHCl₃ (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic extracts were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.

Step 4 Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

A mixture of ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh₃)₄ (0.1 g, 0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT and 25 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.290 g) as a yellow oil.

Step 5 Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 10 mL/10 mL/4 mL at 0° C. A solution of NaNO₂ (0.066 g, 0.96 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h and the solvent was evaporated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na₂SO₄, filtered and concentrated to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.110 g) as yellow oil.

Step 6 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid

Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.1 g) dissolved in MeOH/THF/H₂O (10 mL/10 mL/5 mL) and 70 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO₄, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid (75 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.71 (d, 2H), 7.54 (d, 2H), 6.86 (s, 1H), 6.85 (s, 1H), 3.97 (d, 2H), 2.85 (m, 2H), 2.54 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H), 1.35 (t, 1H), 0.47 (m, 2H), 0.41 (m, 2H).

Example 2495 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid

Step 1 Ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (0.5 g) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,4-dibromobutane (0.24 g, mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered and concentrated under reduced pressure to give ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate (380 mg) as a colorless oil.

Step 2 Ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate (10 g), in dry MeOH (100 mL) Pd (OH)₂ (2 g) was added and the mixture was reduced under an atmosphere of H₂ for 6 h at room temperature. The mixture was filtered through a pad of Celite™, washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (7.5 g) as a thick liquid.

Step 3 Ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl₄ (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic extracts were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.

Step 4 Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate

A mixture of ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd (PPh₃)₄ (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (4.6 g) as a yellow oil.

Step 5 Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate

Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO₂ (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a crude black oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate as yellow oil (1.1 g).

Step 6 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid

Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (80 mg) dissolved in 10 mL of MeOH/THF/H₂O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylic acid (45 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.68 (d, 2H), 7.55 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 3.97 (d, 2H), 2.64 (m, 2H), 1.95 (m, 2H), 1.77 (m, 4H), 1.21 (m, 1H), 0.45 (m, 2H), 0.18 (m, 2H);

Example 2419 2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1 Ethyl 3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate

Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (2 g, 6.5 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.171 g, 7.1 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and cyclopropylmethyl bromide (0.967 g, 7.16 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give ethyl 3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate (1.05 g) as a colorless oil.

Step 2 Ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate

To a stirred solution of ethyl 3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate (1.0 g), in dry MeOH (100 mL) Pd(OH)₂ (500 mg) was added and the mixture was reduced under an atmosphere of H₂ for 6 h at room temperature. The mixture was filtered off through a pad of Celite™, washing with MeOH. The combined filtrates were concentrated under reduced pressure to give ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9 g) as a thick liquid.

Step 3 Ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate

To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9 g, 2.7 mmol) in dry CHCl₃ (50 mL), NBS (0.412 g, 2.3 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.02 g) as a yellow solid.

Step 4 Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.1, 3.3 mmol), 4-trifluoromethylphenylboronic acid (1.26 g, 6.7 mmol), CsF (1.26 g, 8.3 mmol) and Pd (PPh₃)₄ (0.38 g, 0.33 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 50 mL of EtOAc and 50 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.85 g, 82% yield) as a white solid.

Step 5 Ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.85 g, 1.78 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 15 mL/15 mL/2 mL at 0° C. A solution of NaNO₂ (0.185 g, 2.68 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.8 g, 17.8 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2 h. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.528 g) as a yellow oil.

Step 6 2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

The ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (500 mg, 1.01 mmol) dissolved in 20 mL of MeOH/THF/H₂O (10 mL/10 mL/5 mL) and LiOH (57 mg) was added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopropylpropanoic acid (250 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.72 (d, 2H), 7.54 (d, 2H), 7.02 (d, 2H), 4.44 (q, 2H), 3.72 (t, 1H), 1.92 (m, 1H), 1.79 (m, 1H), 1.08 (m, 1H), 0.66 (m, 1H), 0.44 (m, 2H), 0.16 (m, 2H).

Example 2422 Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

Step 1 Ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (3 g, 9.7 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.514 g, 10.7 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.03 mL, 9.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (900 mg) as a colorless oil.

Step 2 Ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (900 mg), in dry MeOH (50 mL), Pd(OH)₂ (400 mg) was added and the mixture reduced under an atmosphere of H₂ for 6 h at room temperature. The mixture was filtered through a pad of Celite™ washing with MeOH, the combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (800 mg) as a thick liquid.

Step 3 Ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.4 g, 8.3 mmol) in dry CHCl₃ (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 hat room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents were dried over Na₂SO₄, filtered and concentrated under educed pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.

Step 4 Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

A mixture of ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh₃)₄ (0.1 g, 0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.290 g) as a yellow oil.

Step 5 Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 10 mL/10 mL/4 mL at 0° C. A solution of NaNO₂ (0.066 g, 0.96 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na₂SO₄, filtered and concentrated to give oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate as a yellow oil (0.110 g).

Step 6 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid

Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.1 g) dissolved in MeOH/THF/H₂O (10 mL/10 mL/5 mL) and 70 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid (75 mg) of the product as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.74 (d, 2H), 7.53 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 4.43 (q, 2H), 2.88 (m, 2H), 2.54 (m, 2H), 2.15 (m, 1H), 1.93 (m, 1H)

Example 2423 1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid

Step 1 Ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (0.5 g, mmol) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,4-dibromobutane (0.24 g, mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate (380 mg) as a colorless oil.

Step 2 Ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate (10 g), in dry MeOH (100 mL) Pd(OH)₂ (2 g) was added and reduced under an atmosphere of H₂ for 6 h at room temperature. The mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (7.5 g) as a thick liquid.

Step 3 Ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl₄ (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.

Step 4 Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate

A mixture of ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoro ethoxy)phenyl)cyclopentanecarboxylate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd(PPh₃)₄ (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (4.6 g) as a yellow oil.

Step 5 Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate

Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO₂ (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylate (1.1 g) as yellow oil.

Step 6 1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid

The ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylate (80 mg) dissolved in 10 mL of MeOH/THF/H₂O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylic acid (45 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.74 (d, 2H), 7.55 (d, 2H), 7.08 (s, 1H), 4.44 (q, 2H), 2.66 (m, 2H), 1.98 (m, 2H), 1.78 (m, 4H).

Example 2418 2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate

Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (4 g, 16.2 mmol) was dissolved in 50 mL anhydrous DMF and NaH (60% wt. in oil, 0.846 g, 21.1 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and isobutyl bromide (2.12 mL, 19.5 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give ethyl 4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5 g) as a colorless oil.

Step 2 Ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl 4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5 g), in dry MeOH (100 mL), Pd(OH)₂ (500 mg) was added and the mixture reduced under an atmosphere of H₂ for 6 h at room temperature. The mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to give ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.2 g) as a thick liquid.

Step 3 Ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.750 g, 2.2 mmol) in dry CHCl₃ (100 mL), NBS (0.320 g, 1.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (700 mg) as a yellow solid.

Step 4 Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

A mixture of ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.70 g, 1.6 mmol), 4-trifluoromethylphenylboronic acid (0.642 g, 3.39 mmol), CsF (0.641 g, 4.2 mmol) and Pd (PPh₃)₄ (0.196 g, 0.16 mmol) in 40 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 35 mL of EtOAc and 35 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (650 mg) as a colorless liquid.

Step 5 Ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (640 mg, 1.3 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 15 mL/15 mL/1 mL at 0° C. A solution of NaNO₂ (0.138 g, 2.0 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.32 g, 13.4 mmol) in water (5 mL) was added drop wise at 0° C. The reaction mixture was heated to 80° C. for 2 h and the mixture was concentrated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na₂SO₄, filtered and concentrated to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (380 mg) as a yellow solid.

Step 6 2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (320 mg, 0.647 mmol) was dissolved in a MeOH/THF/H₂O (10 mL/10 mL/5 mL) mixture, LiOH (163 mg, 3.88 mmol) was added. The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and evaporated under reduced pressure. Purification was achieved by re-crystallization in hexane/ether mixture to give 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (220 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.74 (d, 2H), 7.55 (d, 2H), 7.01 (s, 2H), 4.44 (q, 2H), 3.68 (t, 1H), 1.98 (m, 2H), 1.61 (m, 1H), 1.54 (m, 1H), 0.95 (d, 6H)

Example 1277 2-(5-Chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1 Ethyl 2-(3-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (25 g, 138 mmol) in 375 ml of DCM, sulfuryl chloride (9.48 mL 118 mmol) was slowly added at 0° C. over a period of 30 min. Diethyl ether (19.6 mL) was slowly added reaction mixture at 0° C. and stirring was continued for 30 min at 0° C. The reaction mixture was slowly warmed to 15° C. for 1 h. After completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with 10% NaHCO₃ solution followed by water. The organic layer was dried over Na₂SO₄, filtered and evaporated under vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (15 g) as a thick oil.

Step 2 Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (15 g, 69 mmol) in CCl₄ (270 mL), bromine (11.1 g, 69 mmol) was added slowly (dissolved in 140 mL of CCl₄) at −10° C. over a period of 30 min. The reaction mixture was stirred for another 1 h at −10° C. Upon completion of the reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with saturated Na₂S₂O₃ solution, water, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude compound was purified by re-crystallization using hexane to yield compound ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (7 g, 7 g starting material recovered) as a white solid.

Step 3 Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (6.5 g, 22 mmol), in DMF (100 mL), K₂CO₃ (7.67 g, 55.6 mmol) was added. Trifluoroethyl iodide (13.16 mL, 133 mmol) was added in a drop wise manner to the reaction mixture at RT. The mixture was then heated at 60° C. for 4 h. After completion of reaction, the mixture was poured into water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried over Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography to give compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (6.5 g) as a white solid.

Step 4 Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate

To a suspension of NaH (0.327 g, 60% in paraffin oil, 8.1 mmol) in DMF (100 mL), slowly added a mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g, 6.8 mmol) and cyclopropyl methylbromide (0.718 mL, 7.5 mmol) dissolved in DMF (20 mL) at 0° C. for 15 min under an atmosphere of nitrogen. The reaction mixture was allowed stir at 0° C. for 15 min, upon which the mixture was poured onto crushed ice and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and evaporated. The residue was purified by Flash column chromatography to give compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (2.35 g) as a thick syrup.

Step 5 Ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-methyl phenylboronic acid (0.237 g, 1.74 mmol), Palladium Tetrakis (triphenylphosphine)(0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (375 mg,) as a thick oil.

Step 7 2-(5-Chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

A mixture of ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (370 mg, 0.84 mmol) and lithium hydroxide monohydrate (282 mg, 6.7 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid (200 mg) as a white solid. ¹HNMR (CDCl₃): 7.21-7.42 (m, 6H); 3.87 (q, 2H); 3.65 (t, 1H); 2.39 (s, 3H), 1.93 (m, 1H); 1.88 (m, 1H); 0.66 (m, 1H); 0.42 (m, 2H); 0.12 (m, 1H); 0.1 (m, 1H).

Example 1289 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid Step 1 Ethyl 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate

A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-ethyl phenylboronic acid (225 mg, 1.74 mmol), Palladium Tetrakis (triphenylphosphine)(0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (400 mg) as a thick oil.

Step 2 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

A mixture of ethyl 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (400 mg, 0.88 mmol) and lithium hydroxide monohydrate (222 mg, 5.2 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid (200 mg) as a white solid. ¹HNMR (CDCl₃): 7.42 (d, 2H), 7.38 (s, 1H), 7.22 (d, 2H) 7.20 (s, 1H), 3.85 (q, 2H); 3.66 (t, 1H); 2.73 (q, 2H), 1.93 (m, 1H); 1.88 (m, 1H); 1.29 (t, 3H), 0.66 (m, 1H); 0.42 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).

Example 1313 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid Step 1 Ethyl 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate

A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-thiomethyl phenylboronic acid (293 mg, 1.7 mmol), Palladium Tetrakis (triphenylphosphine)(0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (360 mg) as a thick oil.

Step 2 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid

A mixture of ethyl 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (350 mg, 0.74 mmol) and lithium hydroxide monohydrate (186 mg, 4.44 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid (310 mg) as a white solid. ¹HNMR (CDCl₃): 7.46 (d, 2H), 7.38 (s, 1H), 7.32 (d, 2H), 7.22 (s, 1H), 3.93 (q, 2H); 3.68 (t, 1H); 2.56 (s, 3H), 1.93 (m, 1H); 1.78 (m, 1H); 1.29 (t, 3H), 0.65 (m, 1H); 0.42 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).

Example 1325 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid Step 1 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate

A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-trifluormethoxy phenylboronic acid (310 mg, 1.65 mmol), Palladium Tetrakis (triphenylphosphine)(0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (260 mg) as a thick oil.

Step 2 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (260 mg, 0.50 mmol) and lithium hydroxide monohydrate (186 mg, 4.44 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid (180 mg) as white solid. ¹HNMR (CDCl₃): 7.56 (d, 2H), 7.40 (s, 1H), 7.25 (m, 3H), 3.98 (q, 2H); 3.68 (t, 1H); 2.56 (s, 3H), 1.913 (m, 1H); 1.76 (m, 1H); 1.29 (t, 3H), 0.62 (m, 1H); 0.41 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).

Example 1301 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid Step 1 Ethyl 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate

A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-isopropyl phenylboronic acid (225 mg, 1.74 mmol), Palladium Tetrakis (triphenylphosphine)(0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (400 mg) as thick oil.

Step 2 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid

A mixture of ethyl 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (400 mg, 0.85 mmol) and lithium hydroxide monohydrate (215 mg, 5.1 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid (180 mg) as white solid. ¹HNMR (CDCl₃): 7.44 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s, 1H), 3.86 (q, 2H); 3.67 (t, 1H); 2.98 (m, 1H), 1.93 (m, 1H); 1.78 (m, 1H); 1.28 (d, 6H), 0.66 (m, 1H); 0.43 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).

Example 1280 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid

Step 1 Ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

To a suspension of NaH (0.65 g, 60% in paraffin oil) in DMF (100 mL), slowly added a mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g, 6.8 mmol) and 1,3-dibromo propane (1.61 g, 8.0 mmol) dissolved in DMF (20 mL) at 0° C. for 15 min under an atmosphere of nitrogen. The reaction mixture was allowed stir at 0° C. for 15 min, upon which the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by Flash column chromatography to give ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.12 g) as a thick syrup.

Step 2 Ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate

A mixture of compound ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (500 mg, 1.2 mmol), 4-methyl phenylboronic acid (0.237 g, 1.68 mmol), Palladium Tetrakis (triphenylphosphine)(0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (325 mg) as thick oil.

Step 3 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid

A mixture of ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (300 mg, 0.70 mmol) and lithium hydroxide monohydrate (280 mg, 11.6 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (185 mg, 66%) as white solid. ¹HNMR (CDCl₃): 7.42 (m, 2H); 7.32 (s, 1H), 7.23 (d, 2H), 7.18 (s, 1H), 3.87 (q, 2H); 2.85 (m, 2H), 2.54 (m, 2H), 2.39 (s, 3H), 2.12 (m, 1H); 1.83 (m, 1H).

Step 4 Ethyl 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate

A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500 mg, 1.2 mmol), 4-ethyl phenylboronic acid (225 mg, 1.74 mmol), Palladium Tetrakis (triphenylphosphine)(0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (360 mg) as a thick oil.

Step 5 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid

A mixture of ethyl 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (350 mg, 0.84 mmol) and lithium hydroxide monohydrate (222 mg, 9.2 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (260 mg) as white solid. ¹HNMR (CDCl₃, 500 MHz): 7.42 (d, 2H), 7.38 (s, 1H), 7.22 (d, 2H) 7.20 (s, 1H), 3.85 (q, 2H); 2.82 (m, 2H), 2.71 (q, 2H), 2.52 (m, 2H), 2.15 (m, 1H), 1.91 (m, 1H); 1.27 (t, 3H).

Example 1316 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid Step 1 Ethyl 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate

A mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500 mg, 1.2 mmol), 4-thiomethyl phenylboronic acid (293 mg, 1.7 mmol), Palladium Tetrakis (triphenylphosphine)(0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (342 mg) as thick oil.

Step 2 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid

A mixture of ethyl 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (325 mg, 0.70 mmol) and lithium hydroxide monohydrate (186 mg, 4.44 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (265 mg) as a white solid. ¹HNMR (CDCl₃): 7.46 (d, 2H), 7.38 (s, 1H), 7.32 (d, 2H), 7.19 (s, 1H), 3.93 (q, 2H); 2.83 (m, 2H), 2.53 (s, 3H), 2.32 (m, 2H), 2.13 (m, 1H), 1.93 (m, 1H).

Example 1304 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl) cyclobutane carboxylic acid Step 1 Ethyl 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate

A mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500 mg, 1.2 mmol), 4-isopropyl phenylboronic acid (245 mg, 1.68 mmol), Palladium Tetrakis (triphenylphosphine)(0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (425 mg) as thick oil.

Step 2 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid

A mixture of ethyl 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (400 mg, 0.88 mmol) and lithium hydroxide monohydrate (215 mg, 5.1 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (289 mg) as white solid. ¹HNMR (CDCl₃): 7.44 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s, 1H), 3.86 (q, 2H); 2.99 (m, 1H), 2.86 (m, 2H), 2.52 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H); 1.28 (d, 6H).

Example 1833 2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid

Step 1 Ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropyl propanoate

To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.2 g, 4.0 mmol) in dry CCl₄ (60 mL), NCS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield compound ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropyl propanoate (0.920 g) as a yellow solid.

Step 2 Ethyl 2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate

Ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropyl propanoate (0.9 g, 2.6 mmol) was dissolved in a mixture of AcCN/H₂O/HCl (96%) 25 mL/25 mL/1 mL at 0° C. A solution of NaNO₂ (0.277 g, 4.02 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of KI (4.5 g, 26.8 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with 10% sodium thiosulfate (2×50 mL), water (100 mL) followed by brine (100 mL). The solution was dried over Na₂SO₄, filtered and concentrated to give crude black oil which was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl 2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.1 g, 90.9%) as yellow oil.

Step 3 Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropyl propanoate

A mixture of ethyl 2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.1 g, 2.4 mmol), 4-trifluoromethylphenylboronic acid (0.928 g, 4.9 mmol), CsF (0.926 g, 6.1 mmol) and Pd (PPh₃)₄ (0.283 g, 0.245 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 40 mL of EtOAc and 40 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropyl propanoate (0.650 g) as a yellow oil.

Step 4 2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid

Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropyl propanoate (0.65 g, 1.31 mmol) was dissolved in 25 mL of MeOH/THF/H₂O (10:10:5, vvl), LiOH (0.252 g, 10.5 mmol) was added. The reaction mixture was stirred for 5 h at room temperature and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over Na₂SO₄, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the 2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid (0.585 g) as a white solid. ¹H NMR (500 MHz, CDCl₃/TMS): δ 7.71 (d, 2H), 7.39 (d, 2H), 7.22 (s, 1H), 6.91 (s, 1H), 4.23 (q, 2H), 3.72 (t, 1H), 1.93 (m, 1H), 1.82 (m, 1H), 0.81 (m, 1H), 0.52 (m, 2H), 0.15 (m, 2H).

Example 1836 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutane carboxylic acid

Step 1 Ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.0 g, 6.3 mmol) in dry CHCl₃ (30 mL), NCS (0.842 g, 6.3 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.4 g) as thick syrup.

Step 2 Ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

Ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.45 g, 1.27 mmol) was dissolved in a mixture of AcCN/H₂O/HCl (96%) 15 mL/10 mL/3.1 mL at 0° C. A solution of NaNO₂ (0.132 g, 1.91 mmol) in water (1 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of KI (2.11 g, 12.7 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 80° C. for 1 h. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with 10% sodium thiosulfate (2×50 mL), water (100 mL) followed by brine (100 mL). The solution was dried over Na₂SO₄, filtered and concentrated to give crude black oil which was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.350 g) as yellow oil.

Step 3 Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate

A mixture of ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.35, 7.35 mmol), 4-trifluoromethylphenylboronic acid (0.277 g, 1.47 mmol), CsF (0.277 g, 1.83 mmol) and Pd (PPh₃)₄ (0.084 g, 0.36 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 20 mL of EtOAc and 20 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate (0.182 g) as a colorless oil.

Step 4 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylic acid

Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate (0.2 g, 0.41 mmol) was dissolved in 25 mL of MeOH/THF/H₂O (10:10:5, vvl), LiOH (0.10 g, 4.1 mmol) was added. The reaction mixture was stirred for 5 h at room temperature and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over Na₂SO₄, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the compound 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylic acid (0.06 g) as a white solid. ¹H NMR (500 MHz, CDCl₃/TMS): δ 7.72 (d, 2H), 7.41 (d, 2H), 7.19 (s, 1H), 6.79 (s, 1H), 4.23 (q, 2H), 3.92 (m, 2H), 2.58 (m, 2H), 2.19 (m, 1H), 1.97 (m, 1H);

Example 1837 Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate

Step 1 Ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 3.6 mmol) in dry CHCl₃ (60 mL), NCS (0.411 g, 3.08 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.860 g) as a thick syrup.

Step 2 Ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

Ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.86 g, 2.3 mmol) was dissolved in a mixture of AcCN/H₂O/HCl (96%) 10 mL/8 mL/2.1 mL at 0° C. A solution of NaNO₂ (0.243 g, 3.5 mmol) in water (1 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of KI (3.9 g, 23.5 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 80° C. for 1 h. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with 10% sodium thiosulfate (2×50 mL), water (100 mL) followed by brine (100 mL). The solution was dried over Na₂SO₄, filtered and concentrated to give crude black oil which was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.580 g) as pale yellow oil.

Step 3 Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate

A mixture of ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.58, 1.2 mmol), 4-trifluoromethylphenylboronic acid (0.56 g, 2.4 mmol), CsF (0.46 g, 3.0 mmol) and Pd (PPh₃)₄ (0.14 g, 0.12 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 25 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate (0.480 g) as a color less oil.

Step 4 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylic acid

Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentane carboxylate (0.32 g, 0.64 mmol) was dissolved in 25 mL of MeOH/THF/H₂O (10:10:5, vvl), LiOH (0.163 g, 3.88 mmol) was added. The reaction mixture was stirred for 5 h at room temperature and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over Na₂SO₄, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (0.220 g, 73%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.69 (d, 2H), 7.41 (d, 2H), 7.26 (s, 1H), 6.92 (s, 1H), 4.22 (q, 2H), 3.71 (m, 2H), 1.98 (m, 2H), 1.81 (m, 4H).

Example 1832 2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.25 g, 0.75 mmol) in dry CHCl₃ (20 mL), NCS (0.08 g, 0.6 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.15 g) as thick syrup.

Step 2 Ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate

Ethyl 2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.7 g, 1.9 mmol) was dissolved in a mixture of AcCN/H₂O/HCl (96%) 20 mL/20 mL/1.3 mL at 0° C. A solution of NaNO₂ (0.197 g, 2.8 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of KI (3.16 g, 19.0 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 80° C. for 1 h. The reaction mixture was extracted with EtOAc (3×100 mL), and the combined organic layers were washed with 10% sodium thiosulfate (2×50 mL), water (100 mL) followed by brine (100 mL). The solution was dried over Na₂SO₄, filtered and concentrated to give crude black oil which was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.35 g) as pale yellow oil.

Step 3 Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate

A mixture of ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.5, 1.04 mmol), 4-trifluoromethylphenylboronic acid (0.96 g, 2.09 mmol), CsF (0.395 g, 2.6 mmol) and Pd (PPh₃)₄ (0.121 g, 0.104 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 25 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate (0.265 g,) as a colorless oil.

Step 4 2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic acid

Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate (0.35 g, 0.733 mmol) was dissolved in 25 mL of MeOH/THF/H₂O (10:10:5, vvl), LiOH (0.176 g, 7.33 mmol) was added. The reaction mixture was stirred for 5 h at room temperature and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over Na₂SO₄, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the compound 2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic acid (0.085 g) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.69 (d, 2H), 7.41 (d, 2H), 7.20 (s, 1H), 6.86 (s, 1H), 4.23 (q, 2H), 3.71 (t, 1H), 2.01 (m, 1H), 1.73 (m, 1H), 1.58 (m, 1H), 0.98 (d, 6H).

Example 1908 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutane carboxylic acid

2-(Cyclopropylmethoxy)-4-fluoro-1-nitrobenzene

Cyclopropylmethanol (15 g, 207 mmol) was added to a stirred suspension of NaH (60% in mineral oil, 8.37 g) in 200 mL THF over 15 min at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then poured into ice water. The reaction mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure to give 22.0 g of product as orange oil (86%).

Step 2 Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate

Diethyl malonate (9.8 g, 1.1 eq.) was added to a stirred suspension of sodium hydride (60% in mineral oil, 2.09 g) in 88 mL DMF over 15 min. at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq.) in DMF (88 mL) was added drop wise at 0° C., and the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into ice water and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO₄). Evaporation of solvent under reduced pressure gave 10.0 g of crude product which was purified by silica gel chromatography (hexane/EtOAc) gave 7.0 g of the desired product (42%)

¹H-NMR (CDCl₃, 200 MHz): 0.4 (m, 2H), 0.71 (m, 2H), 1.3 (m, 1H), 1.3 (t, 6H), 3.96 (d, 2H), 4.25 (q, 4H), 4.5 (s, 1H), 7.02 (d, 1H), 7.18 (s, 1H), 7.81 (d, 2H).

Step 3 Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate

i) Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl) malonate (10 g) was dissolved in 100 mL ethanol and cooled to 0° C., NaOH solution (4 eq) was added slowly to the reaction mixture for about 15 min. The reaction mixture was heated gently up to 60° C. for 5 h. Progress of the reaction was monitored by TLC analysis. After complete conversion of starting material solvent was evaporated under reduced pressure, the residue dissolved in H₂O, acidified with 6N HCl to pH-2. The solid material was collected via filtration, washed with water, dried under reduced pressure to yield 6.5 g (90%) of 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid as a yellow solid.

¹H-NMR (CDCl₃, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H), 1.28 (m, 1H), 3.71 (s, 2H), 4.01 (d, 2H), 7.02 (d, 1H), 7.23 (s, 1H), 7.81 (d, 1H).

ii) 2-(3-(Cyclopropylmethoxy)-4-nitrophenyl)acetic acid (6.5 g) was taken up in an ethanolic HCl solution (50 mL, 25%) and refluxed for 4 h, monitored by TLC. The reaction mixture was concentrated in vacuo to dryness and dissolved in ethyl acetate. The mixture was washed with NaHCO₃ solution, dried over NaSO₄ and concentrated in vacuo to give crude yellow solid which was purified by recrystallization to give the desired product (4.2 g).

¹H-NMR (CDCl₃, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H), 1.12 (t, 3H), 1.28 (m, 1H), 3.71 (s, 2H), 4.01 (d, 2H), 4.21 (q, 2H), 7.02 (d, 1H), 7.23 (s, 1H), 7.81 (d, 1H).

Step 4 Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH (100 mL) was added Pd(OH)₂ (2 g). The mixture was hydrogenated under a H₂ atmosphere for 6 h at room temperature. The reaction mixture was filtered through a pad of Celite™, washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield 7.5 g of the desired product as an oil.

¹H-NMR (CDCl₃, 200 MHz): 0.38 (m, 2H), 0.61 (m, 2H), 1.23 (m, 1H), 1.23 (t, 3H), 3.51 (s, 2H), 3.80 (d, 2H), 4.16 (q, 2H), 6.72 (m, 3H).

Step 5 Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol) in dry CCl₄ (60 mL), NCS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na₂SO₄, filtered and concentrated in vacuo.

The crude reaction mixture was purified by column chromatography to yield Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg) as a yellow solid.

Step 6 Ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate

Ethyl-2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)-acetate (2.5 g, 10.0 mmol) was dissolved in a mixture of AcCN/H₂O/HCl (96%) 50 mL/50 mL/25 mL at 0° C. A solution of NaNO₂ (3.2 g, 1.16 eq) in water (40 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of KI (30 g, 30.1 mmol) in water (80 mL) was added drop wise at 0° C. The reaction mixture was heated to 50° C. for 2.5 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with 10% sodium thiosulfate (2×50 mL), water (300 mL) followed by brine (300 mL). The solution was dried over Na₂SO₄, filtered and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (1.2 g)

Step 7 Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate

A mixture of compound ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (5.1 g, 12.9 mmol), 4-trifluoromethylphenylboronic acid (3.66 g, 19 mmol), CsF (3.9 g, 25.8 mmol) and Pd (PPh₃)₄ (1.5 g, 1.3 mmol) in 100 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (3.2 g) as yellow oil.

Step 8 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutane carboxylic acid

Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (0.5 g, 1.2 mmol) was dissolved in 10 mL anhydrous DMF, NaH (60% wt. in oil, 0.058 g, 2.4 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.5 mL) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered and concentrated under reduced pressure to give a (320 mg) of colorless oil. The oil was dissolved in 10 mL of EtOH/H₂O (9:1, vvl) and 0.163 g LiOH added. The reaction mixture was refluxed for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutane carboxylic acid (0.210 g) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.68 (d, 2H), 7.41 (d, 2H), 7.06 (s, 1H), 6.78 (s, 1H), 3.78 (d, 2H), 2.86 (m, 2H), 2.58 (m, 2H), 2.16 (m, 1H), 1.95 (m, 1H), 1.03 (m, 1H), 0.46 (m, 2H), 0.18 (m, 2H).

Example 1909 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentane carboxylic acid 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentane carboxylic acid

Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (0.5 g,) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.058 g, 2.4 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,4-dibromobutane (0.24 g) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered and concentrated under reduced pressure to give a (320 mg, 0.64 mmol) of colorless oil. The oil was dissolved in 10 mL of EtOH/H₂O (9:1, vvl) and LiOH (0.163 g, 3.88 mmol) added. The reaction mixture was refluxed for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) to give 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentane carboxylic acid (220 mg) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.68 (d, 2H), 7.41 (d, 2H), 7.16 (s, 1H), 6.91 (s, 1H), 3.78 (d, 2H), 2.66 (m, 2H), 1.97 (m, 2H), 1.79 (m, 4H), 1.03 (m, 1H), 0.46 (d, 2H), 0.18 (d, 2H);

Example 2418 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (2.2 g, 7.8 mmol) was dissolved in 20 mL anhydrous DMF and NaH (60% wt. in oil, 0.189 g, 7.8 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and isobutyl bromide (1.08 g, 7.8 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered and concentrated under reduced pressure to give ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.06 g) of colorless oil.

Step 2 Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.0 g, 5.9 mmol), in dry MeOH (50 mL) Pd(OH)₂ (1.1 g) was added. The mixture was reduced under an atmosphere of H₂ for 6 h at room temperature. The reaction mixture was filtered off through a pad of Celite™, washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.69 g) as a thick liquid.

Step 3 Ethyl 2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.65 g, 5.4 mmol) in dry CCl₄ (60 mL), NBS (0.96 g, 5.4 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield ethyl 2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.5 g) as a yellow solid.

Step 4 Ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

A mixture of ethyl 2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.5 g, 3.9 mmol), 4-trifluoromethylphenylboronic acid (1.1 g, 5.8 mmol), CsF (1.47 g, 7.8 mmol) and Pd (PPh₃)₄ (0.45 g, 0.39 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methyl pentanoate (1.2 g) as a yellow oil.

Step 5 Ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methyl pentanoate (0.2 g, 0.44 mmol) was dissolved in a mixture of AcCN/H₂O/HCl 10 mL/10 mL/1 mL at 0° C. A solution of NaNO₂ (0.039 g, 0.53 mmol) in water (1 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (0.22 g, 2.2 mmol) in water (5 mL) was added drop wise at 0° C. The reaction mixture was heated to 40° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (30 mL) followed by brine (20 mL). The solution was dried over Na₂SO₄, filtered and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.12 g) as a thick oil.

Step 6 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

The ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (120 mg, 0.255 mmol) dissolved in 10 mL of MeOH/THF/H₂O (10 mL/10 mL/5 mL) and LiOH (30 mg, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM:MeOH 9:1) gave 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (89 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.68 (d, 2H), 7.55 (d, 2H), 6.92 (s, 1H), 6.85 (s, 1H), 3.96 (d, 2H), 3.64 (t, 1H), 1.98 (m, 1H), 1.68 (m, 1H), 1.55 (m, 1H), 1.32 (m, 1H), 0.91 (d, 6H), 0.64 (m, 2H), 0.42 (m, 2H);

Example 3205 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoic acid

Step 1 Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (12 g, 40.816 mmol) in DMSO (80 mL) were added K₂CO₃ (14.08 g, 102.020 mmol) and cyclopropylmethylbromide (5 mL, 4.880 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 80° C. temperature over a period of 14 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and quenched with water and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×75 mL), brine and dried over Na₂SO₄. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (10 g) yellow solid.

Step 2 Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate

To a stirred solution of NaH (0.3 g, 12.5 mmol) in DMF (10 mL) was added ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (2.0 g, 5.70 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. To the reaction mixture was added 2-bromo ethyl methyl ether (0.87 g, 6.25 mmol) and stirred at 0° C. for 30 min. After completion of starting material (by TLC), the reaction mixture was diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×50 mL). Combined organic layers were washed with water (3×25 mL), brine and dried over anhydrous Na₂SO₄. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate (560 mg) as an off white solid.

Step 3 Ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate (2.3 g, 5.660 mmol) in a mixture of DMF (50 mL) and water (5 mL) were added Cs₂CO₃ (6.4 g, 19.815 mmol), Pd(TPP)₄ (1.3 g, 1.120 mmol) and 4-(trifluoromethyl)phenyl boronic acid (1.29 g, 6.780 mmol) at RT under N₂ atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), filtered off the catalyst and celite bed was washed with EtOAc and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na₂SO₄. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate (1.2 g) as an off white solid.

Step 4 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoic acid

To a stirred solution of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate (0.3 g, 0.638 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H₂O (53 mg, 12.030 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (20 mL), brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoic acid (100 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ ppm 7.68 (m, 4H), 7.40 (s, 1H), 7.20 (s, 1H), 3.80 (t, 1H), 3.41 (d, 2H), 3.25 (m, 5H), 2.39 (m, 1H), 1.99 (m, 1H), 0.95 (m, 1H), 0.4 (d, 2H), 0.0 (m, 2H).

Example 3206 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid

Step 1 Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl pentanoate

To a stirred solution of NaH (0.76 g, 15.82 mmol) in DMF (50 mL) was added compound 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoic acid (5.0 g, 14.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. To the reaction mixture was added isobutyl bromide (2.93 g, 21.57 mmol) and stirred at 0° C. for 1 h. After completion of starting material (by TLC), diluted with water (40 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na₂SO₄. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl pentanoate (5.0 g) as a liquid.

Step 2 Ethyl 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl pentanoate (0.5 g, 1.239 mmol) in a mixture of DMF (10 mL) and water (5 mL) were added Cs₂CO₃ (1.4 g, 4.325 mmol), Pd (TPP)₄ (286 mg, 2.475 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (355 mg, 1.363 mmol) at RT under N₂ atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), the solids were removed via filtration through a bed of Celite™ was washing with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford ethyl 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (100 mg) as an off white solid.

Step 3 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid

To a stirred solution of ethyl 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.1 g, 0.218 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H₂O (45 mg, 1.090 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid (39 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 9.05 (s, 1H), 8.2 (m, 2H), 7.73 (m, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 3.63 (t, 1H), 3.40 (d, 2H), 1.99 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 0.93 (m, 7H), 0.38 (d, 2H), −0.5 (d, 2H).

Example 514 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid Step 1 Ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.5 g, 1.240 mmol) in a mixture of DMF (20 mL) and water (5 mL) were added Cs₂CO₃ (1.4 g, 4.342 mmol), Pd(TPP)₄ (286 mg, 2.480 mmol) and 5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (355 mg, 1.364 mmol) at RT under N₂ atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), the solids were removed via filtration through a bed of Celite™ was washing with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (250 mg) as an off white solid.

2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid

To a stirred solution of ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.25 g, 0.565 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H₂O (118.7 mg, 2.828 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford compound-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid (152 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 7.92 (s, 1H), 7.85 (m, 1H), 7.72 (m, 1H), 7.46 (s, 1H), 7.25 (s, 1H), 3.65 (t, 1H), 3.48 (d, 2H), 1.95 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 1.22 (m, 1H0, 0.93 (d, 6H), 0.39 (d, 2H), 0.0 (m, 2H).

Example 524 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid Step 1 Ethyl 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.5 g, 1.239 mmol) in a mixture of DMF (10 mL) and water (5 mL) were added Cs₂CO₃ (1.4 g, 4.325 mmol), Pd(TPP)₄ (286 mg, 2.475 mmol) and 5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]thiazdiazole (355 mg, 1.363 mmol) at RT under N₂ atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), the solids were removed via filtration through a bed of Celite™ was washing with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford ethyl 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (222 mg) as an off white solid.

Step 2 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid

To a stirred solution of ethyl 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.22 g, 0.479 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H₂O (60.3 mg, 1.438 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methyl pentanoic acid (105 mg, 50.0%) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 8.18 (s, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.42 (s, 1H), 7.18 (s, 1H), 3.68 (t, 1H), 3.43 (d, 2H), 2.00 (m, 1H), 1.70 (m, 1H), 1.58 (m, 1H), 0.98 (d, 6H), 0.88 (m, 1H), 0.38 (d, 2H), 0.0 (m, 2H).

Example 3207 2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate

To a stirred compound ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (1.0 g, 3.174 mmol) in DCM (15 ml) chlorosulfonic acid (2 mL, 28.571 mmol) was added. The reaction mixture was stirred for 14 h at 80° C. under N₂ atmosphere. After completion of starting material (by TLC), the reaction mixture was quenched with NaHCO₃ solution and extracted with DCM (3×100 mL). Combined organic layers were washed with water (3×75 mL), brine and dried over Na₂SO₄, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate (0.5 g) as a liquid.

Step 2 Ethyl 2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate (0.73 g, 1.765 mmol) in THF (20 mL) was added N,N-dimethylamine solution (5.2 mL, 10.592 mmol) at RT under inert atmosphere. The reaction mixture was stirred at RT over a period of 14 h. After completion of starting material (by TLC), the reaction mixture was quenched with water and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×75 mL), brine and dried over Na₂SO₄. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate (0.6 g) as a pale yellow liquid.

Step 3 Ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate (0.75 g, 1.77 mmol) in DMSO (25 mL) were added K₂CO₃ (367 mg, 2.106 mmol) and cyclopropylmethylbromide (0.2 mL, 2.13 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 80° C. temperature over a period of 14 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and quenched with water and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×75 mL), brine and dried over Na₂SO₄. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate (350 mg) as a liquid.

Step 4 2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

To a stirred solution of 2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate (0.5 g, 1.049 mmol) in a mixture of DMF (10 mL) and water (5 mL) were added Cs₂CO₃ (1.19 g, 3.670 mmol), Pd(TPP)₄ (243 mg, 0.209 mmol) and 4-(trifluoromethyl)phenylbornate (220 mg, 1.150 mmol) at RT under N₂ atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), filtered off the catalyst and celite bed was washed with EtOAc and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na₂SO₄. After filtration and concentration in vacuo, the crude material was purified by column chromatography to afford 2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (100 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 7.83 (s, 1H), 7.72 (m, 4H), 7.51 (s, 1H), 3.73 (m, 1H), 3.38 (d, 2H), 2.95 (s, 3H), 2.87 (s, 3H), 2.01 (m, 1H), 1.65 (m, 1H), 1.51 (m, 1H), 0.91 (m, 7H), 0.40 (d, 2H), 0.00 (m, 2H).

Step 5 Ethyl 2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

To a stirred solution of ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (1.0 g, 2.227 mmol) in a mixture of HCl: H2O (0.81 mL, 6.681 mmol) was added NaNO₂ (0.180 g, 2.672 mmol). After being stirred for 1 h at 0° C. then added KI (3.69 g, 22.271 mmol) at 0° C. under inert atmosphere. The reaction mixture was stirred at 100° C. temperature over a period of 2 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×75 mL), brine and dried over Na₂SO₄. After filtration and concentration in vacuo, the crude material was purified by column chromatography to afford ethyl 2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.93 g) as a solid.

Example 3210 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid Step 1 Ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

To a stirred solution of ethyl 2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl) biphenyl-3-yl)-4-methylpentanoate (0.25 g, 0.447 mmol) in NMP (10 mL) was added CuCN (50 mg, 0.536 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 200° C. temperature over a period of 2 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and extracted with EtOAc (3×20 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over Na₂SO₄. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl) biphenyl-3-yl)-4-methylpentanoate (0.125 g) a solid.

Step 2 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

To a stirred solution of ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl) biphenyl-3-yl)-4-methylpentanoate (0.125 g, 0.272 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H₂O (34 mg, 0.816 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by column chromatography to afford 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (50 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 7.70 (m, 4H), 7.61 (s, 1H), 7.51 (s, 1H), 3.71 (t, 1H), 3.55 (m, 2H), 2.00 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H), 1.02 (m, 1H), 0.91 (d, 6H), 0.45 (m, 2H), 0.05 (m, 2H).

Example 3208 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

To a stirred solution of ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (1.0 g, 2.604 mmol) in a mixture of HCl: H₂O (0.86 mL, 10.4 mmol) and THF (10 mL) was added NaNO₂ (0.215 g, 3.92 mmol). After being stirred for 1 h at 0° C. then added NaSMe (368 mg, 0.260 mmol) at 0° C. under an inert atmosphere. The reaction mixture was stirred at RT over a period of 14 h. After complete consumption of starting material (by TLC), the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×75 mL), brine and dried over Na₂SO₄. After filtration and concentration under vacuo, the crude material was purified by column chromatography to afford ethyl 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.93 g) as a solid.

Step 2 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

To a stirred solution of ethyl 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (80 mg, 0.166 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H₂O (20 mg, 0.832 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuo. The crude material was purified by column chromatography to afford 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (38 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 7.75 (d, 2H), 7.65 (d, 2H), 7.31 (s, 1H), 7.23 (s, 1H), 3.65 (t, 1H), 3.60 (d, 2H), 2.82 (s, 3H), 1.98 (m, 1H), 1.65 (m, 1H), 1.5 (m, 1H), 1.22 (m, 1H), 0.9 (d, 6H), 0.38 (d, 2H), 0.01 (d, 2H).

Example 3209 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylbutanoic acid Step 1 Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate

To a stirred solution of NaH (40 mg, 0.830 mmol) in DMF (5 mL) was added compound ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (300 mg, 0.728 mmol) and stirred at 0° C. for 1 h. To the reaction mixture at 0° C. was added isopropyl bromide (0.08 mL, 0.880 mmol) and continued stirring at 0° C. over a period of 30 min. After complete consumption of the starting material (by TLC), the reaction mixture was diluted with water (20 mL), acidified with 1N Hcl (pH=5) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×15 mL), brine and dried over anhydrous Na₂SO₄. After filtration and concentration under educed pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate (120 mg) as a liquid.

Step 2 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylbutanoic acid

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate (0.12 g, 0.260 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H₂O (75 mg, 1.320 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of the starting material, as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude material was purified by column chromatography to afford ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylbutanoate (100 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 7.66 (m, 4H), 7.41 (s, 1H), 7.20 (s, 1H), 3.41 (d, 2H), 3.15 (d, 1H), 2.3 (m, 1H), 1.12 (d, 3H), 0.97 (m, 1H), 0.72 (d, 3H), 0.40 (d, 2H), 0.00 (d, 2H).

Example 482 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoic acid Step 1 Ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate

To a stirred solution of NaH (64 mg, 0.13 mmol) in DMF (15 mL) was added ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (500 mg, 0.12 mmol) and 1,1,1-trifluoro-2-iodoethane (0.304 mL, 0.15 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. After completion of starting material (by TLC), diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×30 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over anhydrous Na₂SO₄. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate (300 mg) as liquid.

Step 2 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoic acid

To a stirred solution of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl) biphenyl-3-yl)-4,4,4-trifluorobutanoate (0.1 g, 0.404 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H₂O (85 mg, 2.024 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL) the combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄ and evaporated under vacuum. The crude material was purified by column chromatography to 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoic acid (38 mg) as sticky syrup. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 7.71 (m, 4H), 7.39 (s, 1H), 7.19 (s, 1H), 3.92 (m, 1H), 3.41 (d, 2H), 3.08 (m, 1H), 2.54 (m, 1H), 0.96 (m, 1H), 0.40 (d, 2H), 0.00 (m, 2H).

The following examples can also be made using analogous procedures as described previously, substituting the appropriate reagents known to those of ordinary skill in the art.

Example 3211 2-(5-chloro-6-(cyclopropylmethoxy)biphenyl-3-yl)-4-methylpentanoic acid Example 3212 2-(5-chloro-6-(2-methoxyethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid Example 3213 2-(5-chloro-6-(cyclopropylmethoxy)-3′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid Example 3214 2-(5-bromo-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid Example 3215 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylpentanoic acid Example 3216 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-phenylpropanoic acid Example 3217 2-(3-(benzo[d]thiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid

The following examples can also be made using analogous procedures as described previously, substituting the appropriate reagents known to those of ordinary skill in the art.

Examples 464, 474, 480, 481, 483, 485, 488, 489, 494, 504, 1292, 1334, 2490, 2708, 3211, 3212, 3213, 3214, 3215, 3216 and 3217

Pharmacology Experimental Measurement of Aβ in vitro

The Aβ peptide is proteolytically derived from a larger integral membrane amyloid precursor protein (APP). The production of Aβ is derived from proteolytic cleavages at its N- and C-termini within β-APP by the β and γ-secretase activities, respectively. Transfected cells overexpressing β-APP or its equivalent producing the Aβ peptide can be used to monitor the effects of synthetic compounds on the production of Aβ.

To analyze a compound's effects on the concentrations of the various products of the γ-secretase cleavage activity, the Aβ peptides, various methods known to a person skilled in the art are available. Examples of such methods, but not limited to, include mass-spectrometric identification as described by Wang et al, 1996, J. Biol. Chem. 271:31894-31902) or detection by specific antibodies using, for example, ELISA's.

Examples of such assays for measuring the production of Aβ_(total), Aβ₄₀ and Aβ₄₂ by ELISA include but are not limited to those described by Vassar et al., 1999, Science 286:735-741. Suitable kits containing the necessary antibodies and reagents for such an analysis are available, for example, but not limited to the Genetics Company, Wako, Covance, and Innogenetics. The kits are essentially used according to the manufacturers recommendations similar to the assay that is described by Citron et al., (1997) Nature Medicine 3:67-72 and the original assay described by Seubert et al., (1992) Nature 359:325-327.

Screening was carried out using the human embryonic kidney cell line HEK-293 overexpressing an amyloid precursor protein (APP) transgene grown in Pro-293a CDM media (BioWhittaker). Cells were grown to approximately 70-80% confluency subsequent to the addition of test compounds. The growth media was aspirated or removed, the cells washed, and replaced with 100 μl of compound, appropriately diluted in serum free media. The plates are then incubated for 16-18 hours at 37° C.

Conditioned Medium samples are removed for analysis/quantitation of the various Aβ peptide levels by differential ELISA's as described in accompanying instructions to the kits. Those compounds examined which do not demonstrate any overt toxicity or non-specific inhibitory properties are investigated further for their Aβ inhibitory effects and form the basis of medicinal chemistry efforts and to study the effect of the compounds in different experimental conditions and configurations.

Table 14 shows representative in vitro data (HEK 293) EC₅₀ data for compounds of the disclosure where:

A indicates a compound has an EC₅₀ for lowering Aβ42 of <1 μM B indicates a compound has an EC₅₀ for lowering Aβ42 of >1 μM but <5 μM C indicates a compound has an EC₅₀ for lowering Aβ42 of >5 μM

TABLE 14 Example # Activity 264 A 414 A 415 A 419 A 464 A 474 A 480 A 481 A 482 A 483 A 484 A 485 A 488 A 489 A 494 A 504 A 514 A 524 A 534 A 554 A 724 A 754 B 1055 A 1268 A 1269 A 1270 A 1271 A 1272 A 1277 A 1280 A 1289 A 1292 A 1301 A 1304 A 1313 A 1316 A 1325 A 1334 A 1832 A 1833 A 1836 A 1837 A 1904 A 1905 A 1908 A 1909 A 1976 A 2418 A 2419 A 2422 A 2423 A 2490 A 2491 A 2494 A 2495 A 2708 A 2959 A 2995 A 3200 A 3201 A 3202 B 3203 A 3204 A 3205 A 3206 A 3207 B 3208 A 3209 A 3210 A 3211 A 3212 A 3213 A 3214 A 3215 A 3216 A 3217 B

Table 15 shows individual EC₅₀ values for representative compounds of the disclosure.

TABLE 15 EC₅₀ (Aβ42) HEK 293 Example # Compounds Name (μM) 484 2-(5-chloro-6-(cyclopropylmethoxy)-4′- 0.069 (trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid 514 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4- 0.274 (cyclopropylmethoxy)phenyl)-4-methylpentanoic acid 2959 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-chloro-5- 0.298 (2-cyclopropylethyl)phenyl)-4-methylpentanoic acid 2995 2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-chloro-5- 0.220 (2-cyclopropylethyl)phenyl)-4-methylpentanoic acid 3210 2-(5-cyano-6-(cyclopropylmethoxy)-4′- 0.275 (trifluoromethyl)biphenyl-3-yl)-4- methylpentanoic acid

Experimental Procedures for Rat Primary Cortical Culture-Based Abeta₁ _(→) _(42/1) _(→x) ELISAs

Rat primary neocortical cultures are established through the dissection of the neocortices from 10-12 E17 embryos harvested from time-pregnant SD (Sprague Dawley) rats (Charles River Laboratories). Following dissection, the combined neocortical tissue specimen volume is brought up to 5 mL with dissection medium (DM; 1×HBSS (Invitrogen Corp., cat #14185-052)/10 mM HEPES (Invitrogen Corp., cat #15630-080)/1 mM Sodium Pyruvate (Invitrogen Corp., cat #11360-070)) supplemented with 100 uL Trypsin (0.25%; Invitrogen Corp., cat #15090-046) and 100 uL DNase I (0.1% stock solution in DM, Roche Diagnostics Corp., cat #0104159), undergoing digestion via incubation at 37° C. for 10 minutes. Digested tissue is washed once in plating medium (PM; NeuroBasal (Invitrogen Corp., cat #21103-049)/10% Horse Serum (Sigma-Aldrich Co., cat # H1138)/0.5 mM L-Glutamine (Invitrogen Corp., cat #25030-081)), then resuspended in a fresh 10 mL PM volume for trituration. Trituration consists of 18 cycles with a 5 mL-serological pipet, followed by 18 cycles with a flame-polished glass Pasteur pipet. The volume is elevated to 50 mL with PM, the contents then passed over a 70 um cell-strainer (BD Biosciences, cat #352350) and transferred directly to a wet-ice bath. The cell-density is quantified using a hemacytometer, and diluted to allow for the plating of 50000 cells/well/100 uL in pre-coated 96-well PDL-coated plates (Corning, Inc., cat #3665). Cells are incubated for 4-5 hours at 37° C./5% CO₂, after which time the entire volume is exchanged to feeding medium (FM; NeuroBasal/2% B-27 Serum-free supplement (Invitrogen Corp., cat #17504-044)/0.5 mM L-Glutamine/1% Penicillin-Streptomycin (Invitrogen Corp., cat #15140-122)). The cultures undergo two 50% fresh FM exchanges, after 3 days in vitro (DIV3), and again at DIV7.

Human C-terminal recognition-site Abeta₁ _(→) ₄₂ and Rat N-terminal recognition-site Abeta₁ _(→) _(x) capture-antibodies, diluted 1:300 in 0.05M Carbonate-Bicarbonate buffer (Sigma-Aldrich Co., C-3041), are use to coat (100 uL/well) flat-bottomed F96 MicroWell™ (MaxiSorp™ surface) plates (Nalge Nunc International, cat #439454), and incubated overnight at 4° C. for eventual use in the ELISA assay. Compounds to be screened are solubilized in dimethyl sulphoxide (DMSO, Sigma-Aldrich Co., cat #15493-8), and further diluted in DMSO in an eight-point dose-response format. Into 96-well plates, dose-response compound dilutions (1000× the desired final concentration) are stamped out at 2 uL/well, in duplicate (up to 3 compounds/plate), as a daughter plate. In addition, DMSO and N—[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor (GSI), are incorporated as solvent and positive controls, respectively. With the assistance of liquid-handling automation, the compound daughter plate is diluted 1:500 with warmed FM, and two DIV8 culture plates are leveled to 60 uL/well, and immediately overlaid with 60 uL/well of the 2× diluted daughter plate. The plates are returned to the 37° C./5% CO₂-incubator for 24 hours.

Each coated capture-antibody ELISA plate undergoes 4×250 uL/well Phosphate-buffered saline with 0.05% Tween®-20 SigmaUltra (PBS-T; Fluka, cat #79383/Sigma-Aldrich Co., cat #P7949) washes. The ELISA plates are then overlaid with 120 uL/well PBS-T supplemented with 1% Bovine Serum Albumin Diluent/Blocking solution (BSA; Kirkegaard & Perry Laboratories (KPL), Inc., cat #50-61-01) and incubate at room-temperature on an orbital shaker for a minimum of 2 hours.

Rat Abeta₁ _(→) ₂ and rat Abeta₁ _(→) ₄₀ peptide (American Peptide Co., cat #62-0-84/62-0-86A) DMSO stock solutions are serially-diluted 1:2 in FM yielding a final concentration range of 0-500 pg/mL, to be plated on the respective ELISA plates for determination of the corresponding standard curve, from which concentrations of specific or total Abeta peptides in the presence of a particular drug concentration can be calculated. The conditioned medium from the duplicate culture plates are collected and combined into one round-bottom 96-well transfer plate which is incubated on wet-ice. The culture plates are rinsed once with 120 ul/well FM, and replenished immediately with 100 uL/well FM, being returned to the incubator for 10 minutes. Cell-viability is evaluated by adding 20 uL/well of warmed CellTiter 96® Aq_(ueous) One Solution (MTS/PES; Promega Corp., cat #G3581), and returning the plates to the incubator for 30-90 minutes. Plate absorbance at 492 nm is read on a spectrophotometer, and from which, the ratio of absorbance of compound-treated cells to absorbance of solvent (DMSO)-treated control cells is calculated. The calculation of the corresponding EC₅₀ values is performed following non-linear curve-fitting using GraphPad Prism® software.

For each ELISA plate, a corresponding transfer-plate is created containing 120 uL/well of either the rat Abeta₁ _(→) ₄₂ or rat Abeta₁ _(→) ₄₀ peptide standard solutions, in duplicate, and 110-115 uL/well of the collected conditioned-medium plate, half designated for the Abeta₁ _(→) ₄₂ ELISA, and the other half for the Abeta₁ _(→) _(x) ELISA. The ELISA plates undergo a second set of 4×250 uL/well PBS-T washes, immediately followed by being overlaid with their designated transfer-plate. The ELISA plates incubate on an orbital-shaker for 16-18 hours at 4° C.

Detection antibody solution is prepared by diluting beta-Amyloid 17-24 (4G8) biotinylated monoclonal antibody (Covance, Inc., cat # SIG-39240-200) 1:1500 in PBS-T supplemented with 0.67% BSA. The ELISA plates undergo 4×250 uL/well PBS-T washes, and are overlaid with 100 uL/well of 4G8 diluted detection-antibody solution. The Abeta₁ _(→) ₄₂ ELISA plates are incubated on an orbital-shaker at room-temperature for 90 minutes, the Abeta₁ _(→) _(x) ELISA plates for 60 minutes.

In order to conjugate the biotinylated monoclonal 4G8 antibody, following 4×250 uL/well PBS-T washes, the ELISA plates undergo a one-hour incubation at 100 ul/well with a 1:15000 dilution of Streptavidin-HRP conjugate (Jackson ImmunoResearch Laboratories, Inc., cat #016-030-0840) on an orbital-shaker at room temperature.

Following a final set of 4×250 uL/well PBS-T washes, the ELISA plates are overlaid with 100 ul/well SureBlue 3,3′,5,5′-Tetramethylbenzidine (TMB) Microwell Peroxidase substrate solution (Kirkegaard & Perry Laboratories, Inc., cat #52-00-02), protected from light, and incubate for 20-45 minutes at room temperature. At the point the desired level of development is attained, 100 ul/well of TMB Stop solution (Kirkegaard & Perry Laboratories, Inc., cat #50-85-05) is added, and the plate thoroughly shaken in preparation for reading on a spectrophotometer. SureBlue TMB Microwell Substrate develops a deep blue color in the presence of a peroxidase-labeled conjugate, and turns yellow when stopped by acidification, allowing for plate absorbance at 450 nm to be read. From the calculation of the standard curve, the compound dose-response curves, normalized to DAPT performance, are plotted as % DMSO using GraphPad Prism® software, and the corresponding EC₅₀ values calculated.

Measurement of Aβ 42 in vivo

Compounds of the invention can be used to treat AD in mammal such as a human or alternatively in a validated animal model such as the mouse, rat, or guinea pig. The mammal may not be diagnosed with AD, or may not have a genetic predisposition for AD, but may be transgenic such that it overproduces and eventually deposits Aβ in a manner similar to that seen in the human. Additionally, non-transgenic animals may also be used to determine the biochemical efficacy of the compound, with an appropriate assay.

Compounds can be administered in any standard form using any standard method. For example, but not limited to, compounds can be in the form of liquid, tablets or capsules that are taken orally or by injection. Compounds can be administered at any dose that is sufficient to significantly reduce, for example, levels of Aβ_(total) or more specifically Aβ₄₂ in the blood plasma, cerebrospinal fluid (CSF), or brain.

To determine whether acute administration of the compound would reduce Aβ₄₂ levels in-vivo, two-three month old Tg2576 transgenic mice expressing APP₆₉₅ containing the “Swedish” variant could be used or any other appropriately validated transgenic model. This transgenic mouse displays spontaneous, progressive accumulation of β-amyloid (Aβ) in brain, eventually resulting in amyloid plaques within the subiculum, hippocampus and cortex. Animals of this age have high levels of Aβ in the brain but no detectable Aβ deposition. Mice treated with the compound would be examined and compared to those untreated or treated with vehicle and brain levels of soluble Aβ42 and total Aβ would be quantitated by standard techniques, for example, using ELISA. Treatments may be acute or sub-chronic and treatment periods may vary from hours to days or longer and can be adjusted based on the results of the biochemical endpoint once a time course of onset of effect can be established.

A typical protocol for measuring Aβ or Aβ₄₂ levels from in-vivo samples is shown but it is only one of many variations that could used to detect the levels of Aβ. For example, aliquots of compounds can be dissolved in DMSO (volume equal to 1/10th of the final formulation volume), vortexed and further diluted (1:10) with a 10% (w/v) hydroxypropyl 13 cyclodextrin (HBC, Aldrich, Ref N^(o) 33, 260-7) solution in PBS, where after they are sonicated for 20 seconds.

-   -   Compounds may be administered as a single oral dose given three         to four hours before sacrifice and subsequent analysis or         alternatively could be given over a course of days and the         animals sacrificed three to four hours after the administration         of the final dose     -   Tg2576 mice can be anesthetized with a mixture of         ketamine/xylazine (80/16 mg/kg intraperitoneally). When a deep         level of anesthesia is reached, the mouse's head is secured in a         stereotaxic frame. The skin on the back of the neck is retracted         and the muscles on the back of the neck are removed to expose         the cisterna magna. CSF is collected from the cisterna magna         using a pulled 10 μl micropipette taking care not to contaminate         the CSF with blood. The CSF is immediately diluted 1:10 in 1%         3-[3-cholamidopropyl)-dimethyl-ammonio]-1-propane sulfonate         (CHAPS) [weight per volume in phosphate buffered saline (w/v in         PBS)]containing protease inhibitors (PI's) (Complete, Mini         protease inhibitor cocktail tablets-Roche), quick frozen in         liquid nitrogen and stored at −80° C. until ready for         biochemical analysis.

Blood is collected via cardiac puncture using a 25 gauge needle attached to a 1 ml syringe and was dispensed into a 0.6 ml microtainer tube containing ethylenediaminetetraacetic acid (EDTA). The blood was centrifuged immediately at 4° C. for 5 minutes at 1500×G. The resulting plasma was aliquoted into 0.5 ml microcentrifuge tubes, the aliquots are quick frozen in liquid nitrogen and are stored at −80° C.

The brain is removed after removing the skull and is rinsed with PBS. The cerebellum/brain-stem is removed, frozen, and retained for drug exposure analysis; the remaining brain section was quartered. The rear right quarter, which contained cortex and hippocampus, is weighed, frozen in liquid nitrogen and stored at −80° C. until ELISA analysis. The remaining brain tissue is frozen in liquid nitrogen and stored at −80° C.

For total Aβ or Aβ₄₀ analysis brain tissue is homogenized at a volume of 24 ml/g in cold 1% CHAPS containing protease inhibitors and the resulting homogenates are centrifuged for 1 hour at 100,000×g at 4° C. The supernatant is removed and transferred to a fresh tube and further diluted to 240 ml/g in CHAPS with protease inhibitors.

For Aβ₄₂ analysis brain tissue is homogenized at a volume of 50 ml/g in cold 1% CHAPS containing PI's. Homogenates were spun for 1 hour at 100,000×g at 4° C. The supernatant is removed and transferred to a fresh tube and further to diluted to a final volume 66.7 ml/g in 1% CHAPS with protease inhibitors.

To quantify the amount of human Aβ₄₂ in the soluble fraction of the brain homogenates, commercially available Enzyme-Linked-Immunosorbent-Assay (ELISA) kits can be used (h Amyloid Aβ42 ELISA high sensitive, The Genetics Company, Zurich, Switzerland is just one of many examples). The ELISA is performed according to the manufacturer's protocol. Briefly, the standard (a dilution of synthetic Aβ1-42) and samples are prepared in a 96-well polypropylene plate without protein binding capacity (Greiner bio-one, Frickenhausen, Germany). The standard dilutions with final concentrations of 1000, 500, 250, 125, 62.5, 31.3 and 15.6 pg/ml and the samples are prepared in the sample diluent, furnished with the ELISA kit, to a final volume of 60 μl. Samples, standards and blanks (50 μl) are added to the anti-Aβ-coated polystyrol plate (capture antibody selectively recognizes the C-terminal end of the antigen) in addition with a selective anti-Aβ-antibody conjugate (biotinylated detection antibody) and incubated overnight at 4° C. in order to allow formation of the antibody-Amyloid-antibody-complex. The following day, a Streptavidine-Peroxidase-Conjugate is added, followed 30 minutes later by an addition of TMB/peroxide mixture, resulting in the conversion of the substrate into a colored product. This reaction is stopped by the addition of sulfuric acid (1M) and the color intensity is measured by means of photometry with an ELISA-reader with a 450 nm filter. Quantification of the Aβ content of the samples is obtained by comparing absorbance to a standard curve made with synthetic Aβ1-42.

Similar analysis, with minor modification, can be carried out with CSF (Diluted 1:10 (for a final loading dilution of 1:100) in 1% CHAPS containing PI and plasma samples (Diluted 1:15 in 0.1% CHAPS [w/v in PBS]).

Certain compounds of the disclosure may lower Aβ42 by >15%, in some cases certain compounds may lower Aβ42>25% and in further cases certain compounds may lower Aβ42>40% relative to basal levels.

In Vivo Studies (Rats)

Male Sprague Dawley rats from Harlan, 230-350 g, were used for studies. Fasted rats were dosed via oral gavage, with vehicle (15% Solutol HS 15, 10% EtOH, 75% Water) or compound, at a volume of 10 ml/kg. For PK studies, at fixed time points after dosing, the rats were euthanized with an excess of CO₂. Terminal blood was collected through cardiac puncture, mixed in EDTA tubes, immediately spun (3 min at 11,000 rpm at 4° C.), and snap frozen for plasma collection. A piece of frontal cortex was collected and snap frozen for compound level determination. For A-beta lowering studies, at a determined time point after dosing (Cmax if it is ≧3 hr), rats were euthanized as in the PK studies and plasma was collected as described above. Cerebellum was removed and saved for compound level determination, and the remaining brain was divided into 4 quadrants, snap frozen and saved to examine A-beta peptide levels. Solutol HS 15 was purchased from Mutchler Inc.

Practitioners will also know that similar methods can also be applied to other species such as mice (including transgenic strains such as Tg2576), guinea pig, dog and monkey.

Analysis of In Vivo Aβ Lowering Studies

Compounds of the invention can be used to treat AD in mammal such as a human or alternatively in a validated animal model such as the mouse, rat, or guinea pig. The mammal may not be diagnosed with AD, or may not have a genetic predisposition for AD, but may be transgenic such that it overproduces and eventually deposits Aβ in a manner similar to that seen in the human. Alternatively, non-transgenic animals may also be used to determine the biochemical efficacy of the compound, that is, the effect on the Aβ biomarker, with an appropriate assay.

Compounds can be administered in any standard form using any standard method. For example, but not limited to, compounds can be in the form of liquid, tablets or capsules that are taken orally or by injection. Compounds can be administered at any dose that is sufficient to significantly reduce, for example, levels of Aβ_(total) or more specifically Aβ₄₂ in the blood plasma, cerebrospinal fluid (CSF), or brain.

To determine whether acute administration of the compound would reduce Aβ₄₂ levels in-vivo, two-three month old non-transgenic Sprague-Dawley rats were used. Rats treated with the compound would be examined and compared to those untreated or treated with vehicle and brain levels of soluble Aβ₄₂ and Aβ_(total) would be quantitated by standard techniques, for example, using an immunoassay such as an ELISA. Treatments may be acute or sub-chronic and treatment periods may vary from hours to days or longer and can be adjusted based on the results of the biochemical endpoint once a time course of onset of effect can be established.

A typical protocol for measuring Aβ or Aβ₄₂ levels from in-vivo samples is shown but it is only one of many variations that could used to detect the levels of Aβ.

-   -   Compounds may be administered as a single oral dose given three         to four hours before sacrifice and subsequent analysis or         alternatively could be given over a course of days and the         animals sacrificed three to four hours after the administration         of the final dose.

For total Aβ or Aβ₄₂ analysis brain tissue is homogenized in ten volumes of ice cold 0.4% DEA/50 mM NaCl containing protease inhibitors, e.g., for 0.1 g of brain 1 ml of homogenization buffer is added. Homogenization is achieved either by sonciation for 30 seconds at 3-4W of power or with a polytron homogenizer at three-quarters speed for 10-15 seconds. Homogenates (1.2 ml) are transferred to pre-chilled centrifuge tubes (Beckman 343778 polycarbonate tubes) are placed into a Beckman TLA120.2 rotor. Homogenates are centrifuged for 1 hour at 100,000 rpm (355,040×g) at 4° C. The resulting supernatants are transferred to fresh sample tubes and placed on ice (the pellets are discarded).

The samples are further concentrated and purified by passage over Waters 60 mg HLB Oasis columns according to the methods described (Lanz and Schachter (2006) J. Neurosci Methods. 157(1):71-81; Lanz and Schachter (2008). J. Neurosci Methods. 169(1):16-22). Briefly, using a vacuum manifold (Waters #WAT200607) the columns are attached and conditioned with 1 ml of methanol at a flow rate of 1 ml/minute. Columns are then equilibrated with 1 ml of water. Samples are loaded (800 μl) into individual columns (the Aβ will attach to the column resin).

The columns are washed sequentially with 1 ml of 5% methanol followed by 1 ml of 30% methanol. After the final wash the eluates are collected in 13×100 mm tubes by passing 800 μl of solution of 90% methanol/2% ammonium hydroxide) over the columns at 1 ml/minute. The samples are transferred to 1.5 ml non-siliconized sample tubes are dried in a speed-vac concentrator at medium heat for at least 2 hours or until dry.

The dried samples are either stored at −80° C. or are used immediately by resuspending the pellets in 80 μl of Ultra-Culture serum-free media (Lonza) supplemented with protease inhibitors by vortexing for 10 seconds. Sixty microliters of each sample is transferred to a pre-coated immunoassay plate coated with an affinity purified rabbit polyclonal antibody specific to Aβ₄₂ (x-42). Sixty microliters of fresh supplemented ultraculture is added to the remaining sample and 60 microliters is transferred to a pre-coated and BSA blocked immunoassay plate coated with an affinity purified rabbit polyclonal antibody specific to total rodent Aβ (1-x). Additional standard samples of rodent Aβ/rodent Aβ₄₂ are also added to the plates with final concentrations of 1000, 500, 250, 125, 62.5, 31.3 and 15.6 pg/ml. The samples are incubated overnight at 4° C. in order to allow formation of the antibody-Amyloid-antibody-complex. The following day the plates are washed 3-4 times with 150 microliters of phosphate buffered saline containing 0.05% Tween 20. After removal of the final wash 100 μl of the monoclonal antibody 4G8 conjugated to biotin (Covance) diluted 1:1000 in PBS-T containing 0.67% BSA was added and the plates incubated at room temperature for 1-2 hours. The plates are again washed 3-4 times with PBS-T and 100 μl of a Streptavidin-Peroxidase-Conjugate diluted 1:10,000 from a 0.5 mg/ml stock in PBS-T contained 0.67% BSA is added and the plates incubated for at least 30 minutes. Following a final set of washes in PBS-T, a TMB/peroxide mixture is added, resulting in the conversion of the substrate into a colored product. This reaction is stopped by the addition of sulfuric acid (1M) and the color intensity is measured by means of photometry with an microplate reader with a 450 nm filter. Quantification of the Aβ content of the samples is obtained by comparing absorbance to a standard curve made with synthetic Aβ. This is one example of a number of possible measurable endpoints for the immunoassay which would give similar results.

FIG. 1 demonstrates the desirable effect on Aβ after the administration of example 1301 (2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid) to in C57BL/6 mice when give one dose at 30 mg/kg in a Solutol HS 15:Ethanol:Water (15:10:75) formulation (measuring Aβ at 3 hours).

Pharmacokinetic Analysis Sample Preparation

Plasma samples and standards were prepared for analysis by treating with a 3× volume of acetonitrile containing 500 ng/mL of internal standard (a selected aryl propionic acid). Typically 150 μL of acetonitrile with internal standard was added to 50 μL of plasma. Acetonitrile was added first to each well of a 96-well Phenomenex Strata Impact protein precipitation filter plate followed by the addition of the plasma sample or standard. The filter plate was allowed to sit for at least 15 minutes at room temperature before a vacuum was applied to filter the samples into a clean 96-well plate.

If sample concentrations were observed or predicted to be greater than 1000 ng/mL, plasma samples were diluted with blank plasma 10-150 fold depending on the anticipated concentration and upper limit of quantitation of the analytical method.

Samples of frontal cortex or cerebellum were homogenized then treated in similar manner. To each brain sample, a 4× volume of PBS (pH 7.4) buffer was added along with a 15× volume of acetonitrile (containing internal standard) in a 2 mL screw-cap plastic tube. The tubes were then filled one third of the way with 1 mm zirconia/silica beads (Biospec) and placed in a Mini Bead Beater for 3 minutes. The samples were inspected and if any visible pieces of brain remained, they were returned to the Bead Beater for another 2-3 minutes of shaking The resulting suspension was considered to be a 5-fold dilution treated with a 3× volume of acetonitrile (with internal standard). Calibration standards were prepared in 5-fold diluted blank brain homogenate and precipitated with a 3× volume of acetonitrile immediately after the addition of the appropriate spiking solution (see below). All brain standards and samples were allowed to sit for at least 15 minutes prior to filtering them through a Phenomenex Strata Impact protein precipitation filter plate into a clean 96-well plate.

Spiking solutions for plasma and brain calibration standards were prepared at concentrations of 0.02, 0.1, 0.2, 1, 2, 10, 20, 100 and 200 μg/mL in 50:50 acetonitrile/water. Calibration standards were prepared by taking 190 μL of blank matrix (plasma or brain homogenate) and adding 10 μL of spiking solution resulting in final concentrations of 1, 5, 10, 50, 100, 500, 1000, 5000 and 10,000 ng/mL.

LC-MS/MS Analysis

Precipitated plasma and brain samples were analyzed by LC-MS/MS using a Shimadzu LC system consisting of two LC-10AD pumps and a SIL-HTc autosampler connected to an Applied Biosystems MDS/Sciex API 3200 QTRAP mass spectrometer.

For chromatographic separation, a Phenomenex Luna C-18 3 μM (2×20 mm) column was used with an acetonitrile-based gradient mobile phase. The two mobile phase components were:

Mobile phase A: water with 0.05% (v/v) formic acid and 0.05% (v/v) 5 N ammonium hydroxide.

Mobile phase B: 95:5 acetonitrile/water with 0.05% (v/v) formic acid and 0.05% (v/v) 5 N ammonium hydroxide.

The gradient for each analysis was optimized for the specific compound, but generally, the run started with between 0% and 40% of mobile phase B, ramped up to 100% of mobile phase B over 1-2 minutes, then held there for 2-3 minutes before returning to the initial conditions for 4 minutes to re-equilibrate.

The API 3200 QTRAP mass spectrometer was used in MRM mode with negative electrospray ionization. MRM transitions and mass spec settings were optimized for each compound.

Standard curves were created by quadratic or linear regression with 1/x*x weighting. Calibration standards were prepared 1-10,000 ng/mL, but the highest (and sometimes lowest) standards were often not acceptable for quantitation and only those standards with reasonable back-calculated accuracies were included in the calibration curve. Ideally, only standards with +/−15% of nominal concentration would be included in the fitted standard curve, but occasionally larger deviations were accepted after careful consideration. Sample concentrations below the quantitation range were reported as “BQL”. Concentrations above the curve were usually re-run with larger sample dilutions

Glucuronidation Protocols

Microsomal glucuronidation reactions were conducted using the UGT Reaction Mix solutions (A and B) from BD Biosciences and following the vendor's protocol. 10 μM of test article or control compound was incubated with 0.5 mg/mL of human or rat liver microsomes. Samples were taken at 0 and 60 minutes and acetonitrile was added to terminate the reactions. Samples were analyzed by LC/MS, monitoring for the loss of parent compound and the appearance of glucuronide. Control reactions were run for each compound substituting water for the glucuronic acid solution to monitor for any loss of parent compound due to degradation or unanticipated micro somal reactions.

Hepatocyte experiments were run using cryopreserved human hepatocytes (single donor) obtained from Celsis/In Vitro Technologies. Cells were thawed and counted according to the vendor's protocols using the trypan blue exclusion method to obtain the count of live cells. Test article and control compounds were incubated at a concentration of 5 uM in KHB buffer (Celsis/In Vitro Technologies) containing 1 million cells per mL. Samples were taken at 0, 60 and 120 minutes. The reactions were terminated with addition of acetonitrile. Samples were analyzed by LC/MS, monitoring for the loss of parent compound and the appearance of glucuronide.

Pharmacology

Compounds of the disclosure are gamma secretase modulators (GSMs), i.e., compounds that act to shift the relative levels of Aβ peptides produced by γ-secretase. In some cases the compounds alter the relative levels of Aβ peptides produced by γ-secretase without significantly changing the total level of Aβ peptides produced. Certain compounds of the disclosure modulate γ-secretase activity with respect to APP proteolytic processing and in so doing lower the production of Aβ₄₂ both in vitro in cells and in vivo in animals. In some cases this effect occurs at concentrations that do not significantly impair the viability of cells in vitro and at doses that are well tolerated in vivo. Certain compounds of the disclosure lower Aβ₄₂ secretion in native neuronal and cellular construct assay systems with EC₅₀ values that are below 1 micromolar (Class A compounds, Table 14) while others have EC₅₀ values from 1-5 micromolar (Class B compounds, Table 14) and others have EC₅₀ values greater than 5 micromolar (Class C compounds). Certain compounds of the disclosure do not appear to significantly interfere with γ-secretase related Notch processing activity. Compounds that significantly interfere with γ-secretase related Notch processing activity have been associated with toxic side-effects. Certain compounds of the disclosure have favorable pharmacokinetic (PK) properties in animals. Thus, certain of the compounds are orally bioavailable, penetrate into the brain and have favorable PK parameters including half-life and clearance supporting pharmaceutical application in humans. In turn, certain compounds of the disclosure significantly lower Aβ₄₂ production in the brains of non-transgenic and transgenic animals after single dose and multi-dose oral administration with no overt side effects. For certain compounds of the disclosure single oral doses of <30 milligrams/kilogram are efficacious at lowering Aβ₄₂ production in the brains of rats (e.g. Sprague-Dawley) and wild type mice (e.g. C57BL/6). Certain compounds of the disclosure which lower Aβ₄₂ at doses of <30 milligrams/kilogram appear to be well tolerated and show no overt or clinical chemical toxicity after subchronic 14-day administration at doses >30 milligrams/kilogram/day. Certain compounds of the disclosure have favorable absorption-distribution-metabolism and excretion (ADME) properties. Moreover, certain compounds of the disclosure do not appear to significantly bio-accumulate in tissues especially in the brain. Compounds of Formulas I-IX wherein A=CO₂H show favorable profiles with respect to acylglucoronide (A=CO₂G1u) metabolite formation. The potential for acylglucoronide metabolites to cause of toxicity has been described particularly for non-steroidal anti-inflammatory drugs (NSAIDs) containing carboxylic acid groups (Ebner et at Drug Metabolism and Disposition 1999,27(10), 1143-49). Several such NSAIDs have been removed from the market due to idiosyncratic toxicity in humans and it has been speculated that NSAID idiosyncratic toxicity is related to the relative load and relative reactivity of acylglucoronide metabolites. Therefore, carboxylic acid compounds which are less prone to acylgluconoride formation are expected to be less toxic. As measured using established in vitro assay systems, certain desirable compounds of the disclosure are less prone to acylglucoronidation than NSAID compounds that remain on the market are regarded as safe (e.g., flurbiprofen).

Dosage and Administration

The present disclosure includes pharmaceutical composition for treating a subject having a neurological disorder comprising a therapeutically effective amount of a compound of Formulas I-IX, a derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

The pharmaceutical compositions can be administered in a variety of dosage forms including, but not limited to, a solid dosage form or in a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, buccal, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof. The dosage can be an oral dosage form that is a controlled release dosage form. The oral dosage form can be a tablet or a caplet. The compounds can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration. In one embodiment, the compounds or pharmaceutical compositions comprising the compounds are delivered to a desired site, such as the brain, by continuous injection via a shunt.

In another embodiment, the compound can be administered parenterally, such as intravenous (i.v.) administration. The formulations for administration will commonly comprise a solution of the compound of the Formulas I-IX dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of compound of Formulas I-IX in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For i.v. administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.

In one embodiment, a compound of Formulas I-IX can be administered by introduction into the central nervous system of the subject, e.g., into the cerbrospinal fluid of the subject. The formulations for administration will commonly comprise a solution of the compound of Formulas I-IX dissolved in a pharmaceutically acceptable carrier. In certain aspects, the compound of Formulas I-IX is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar area, or the cisterna magna. In another aspect, the compound of Formulas I-IX is introduced intraocullarly, to thereby contact retinal ganglion cells.

The pharmaceutically acceptable formulations can easily be suspended in aqueous vehicles and introduced through conventional hypodermic needles or using infusion pumps. Prior to introduction, the formulations can be sterilized with, preferably, gamma radiation or electron beam sterilization.

In one embodiment, the pharmaceutical composition comprising a compound of Formulas I-IX is administered into a subject intrathecally. As used herein, the term “intrathecal administration” is intended to include delivering a pharmaceutical composition comprising a compound of Formulas I-IX directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebroventricular injection through a burrhole or cisternal or lumbar puncture or the like (described in Lazorthes et al. Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1: 169-179, the contents of which are incorporated herein by reference). The term “lumbar region” is intended to include the area between the third and fourth lumbar (lower back) vertebrae. The term “cisterna magna” is intended to include the area where the skull ends and the spinal cord begins at the back of the head. The term “cerebral ventricle” is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord. Administration of a compound of Formulas I-IX to any of the above mentioned sites can be achieved by direct injection of the pharmaceutical composition comprising the compound of Formulas I-IX or by the use of infusion pumps. For injection, the pharmaceutical compositions can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the pharmaceutical compositions may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included. The injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.

In one embodiment, the pharmaceutical composition comprising a compound of Formulas I-IX is administered by lateral cerebro ventricular injection into the brain of a subject. The injection can be made, for example, through a burr hole made in the subject's skull. In another embodiment, the encapsulated therapeutic agent is administered through a surgically inserted shunt into the cerebral ventricle of a subject. For example, the injection can be made into the lateral ventricles, which are larger, even though injection into the third and fourth smaller ventricles can also be made.

In yet another embodiment, the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.

For oral administration, the compounds will generally be provided in unit dosage forms of a tablet, pill, dragee, lozenge or capsule; as a powder or granules; or as an aqueous solution, suspension, liquid, gels, syrup, slurry, etc. suitable for ingestion by the patient. Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.

Pharmaceutical preparations for oral use can be obtained through combination of a compound of Formulas I-IX with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

For transmucosal administration (e.g., buccal, rectal, nasal, ocular, etc.), penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

The suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

The compounds can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.

The compounds may also be presented as aqueous or liposome formulations. Aqueous suspensions can contain a compound of Formulas I-IX in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

Oil suspensions can be formulated by suspending a compound of Formulas I-IX in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

For administration by inhalation, the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

In general a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.2 to 10 mg per kilogram body weight per day. The desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.

The compounds can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of neurological disorders. In any event, the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disorder being treated.

Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. (“Remington's After a pharmaceutical composition has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the compounds of Formulas I-IX, such labeling would include, e.g., instructions concerning the amount, frequency and method of administration. 

1-62. (canceled)
 63. A method for treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof.
 64. A method for treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof.
 65. A method for treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising: (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
 66. The method of claim 65, wherein the pharmaceutical composition is in a solid dosage form.
 67. The method of claim 65, wherein the pharmaceutical composition is in an oral dosage form.
 68. The method of claim 67, wherein the oral dosage form is a tablet or a capsule.
 69. The method of claim 68, wherein the oral dosage form is a tablet.
 70. A method for treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising: (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
 71. The method of claim 70, wherein the pharmaceutical composition is in a solid dosage form.
 72. The method of claim 70, wherein the pharmaceutical composition is in an oral dosage form.
 73. The method of claim 72, wherein the oral dosage form is a tablet or a capsule.
 74. The method of claim 73, wherein the oral dosage form is a tablet. 